Novel aminobenzophenone compounds

ABSTRACT

The invention provides novel compounds according to formula I relates to compounds with the general formula I  
                 
said compounds being useful, e.g. in the treatment of inflammatory diseases.

FIELD OF THE INVENTION

The invention relates to a novel class of aminobenzophenones and totheir use in therapy.

BACKGROUND OF THE INVENTION

Aminobenzophenones are well-described in the scientific as well aspatent literature. WO 98/32730, WO 01/05746, WO 01/05749, WO 01/05751and WO 01/05745 all disclose compounds with the common core-structure

wherein the phenyl ring to the right is substituted by an amine.Moreover, WO 01/42189 and WO 02/076447 disclose compounds with a similarstructure, but with no amine substituent in the phenyl ring to theright. Finally, WO 01/90074 and WO 02/083622 disclose compounds wherethe right-most and left-most phenyl rings, respectively are replaced byheterocycles. The compounds of these patent applications are indicatedto be effective inhibitors of interleukin 1β (IL-1β) and tumour necrosisfactor α (TNF-α) secretion in vitro, said compounds being potentiallyuseful for treatment of inflammatory diseases in which the production ofcytokines is involved in the pathogenesis. Apparently,aminobenzophenones exert their effect by an inhibition of p38 MAPkinase, which in turn inhibits the production of IL-1β and TNF-α.

The preparation of structurally related aminobenzophenones useful asdyes for textiles is disclosed in Man-Made Text. India (1987), 30(6),275-6, Man-Made Text. India (1986), 29(5), 224-30, and Man-Made Text.India (1985), 28(11), 425, 427-9, 431.

It has, however, been found that known aminobenzophenones discolour whenexposed to light, probably due to the presence of aromatic amines in ahighly conjugated environment. Hence, when the compounds are applied tothe skin, the skin darkens into a yellow or even blackish shade. Thisis, of course, unacceptable in many situations, and at any rate, itseverely restricts the applicability of aminobenzophenones for treatmentof dermal diseases or states.

It is therefore the purpose of the present invention to provideaminobenzophenones which do not discolour when exposed to light, andwhich thus lend them selves more readily to dermal applications.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to compounds of generalformula I

-   wherein R₁ represents a substituent selected from the group    consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino,    (C₁-C₃)alkyl, (C₂-C₃)olefinic group, (C₁-C₃)alkoxy,    (C₁-C₃)alkylthio, (C₁-C₄)alkylamino and cyano;-   R₂ represents one or more, same or different substituents selected    from the group consisting of hydrogen, halogen, hydroxy, mercapto,    trifluoromethyl, amino, (C₁-C₃)alkyl, (C₂-C₃)olefinic group,    (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, (C₁-C₄)alkylamino,    (C₁-C₃)alkoxycarbonyl, cyano, and nitro;-   R₃ represents one or more, same or different substituents selected    from the group consisting of hydrogen, halogen, hydroxy, mercapto,    trifluoromethyl, cyano, carboxy, carbamoyl, (C₁-C₄)alkyl,    (C₂-C₄)olefinic group, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, and    (C₁-C₄)alkoxycarbonyl;-   R₄ represents one or more, same or different substituents selected    from the group consisting of hydrogen, halogen, hydroxy, mercapto,    trifluoromethyl, amino, (C₁-C₃)alkyl, (C₂-C₃)olefinic group,    (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, (C₁-C₄)alkylamino,    (C₁-C₃)alkoxycarbonyl, cyano, and nitro;-   R₅ represents hydrogen, (C₁-C₆)alkyl and (C₂-C₆)olefinic group;-   R₆ represents hydrogen, (C₁-C₆)alkyl and (C₂-C₆)olefinic group;-   R₇ represents (C₁-C₁₈)alkyl, (C₃-C₈)cyclic hydrocarbon group,    (C₂-C₁₈ )olefinic group, heterocyclyl, (C₂-C₁₈)alkynyl,    (C₁-C₁₈)alkyl-heterocyclyl, (C₁-C₁₈)alkyl-(C₃-C₈)cyclic hydrocarbon    group, (C₂-C₁₈)olefinic group-heterocyclyl, (C₂-C₁₈)olefinic    group-(C₃-C₈)cyclic hydrocarbon group, (C₂-C₁₈)alkynyl-heterocyclyl,    (C₂-C₁₈)alkynyl-(C₃-C₈)cyclic hydrocarbon group; and wherein R₇ may    optionally be substituted by one or more substituents represented by    R₈;-   R₈ represents halogen, hydroxy, mercapto, trifluoromethyl, amino,    (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylamino,    (C₁-C₆)alkoxycarbonyl, (C₁-C₉)trialkylammonium in association with a    pharmaceutically acceptable anion, (C₂-C₁₂)dialkylphosphinoyl,    (C₁-C₆)alkyl(hydroxy)phosphinoyl, (C₂-C₁₂)dialkylphosphinoyloxy,    (C₁-C₆)alkyl(hydroxy)phosphinoyloxy, dihydroxyphosphinoyl,    dihydroxyphosphinoyloxy, cyano, azido, nitro, —CHO, —COOH, —CONH₂,    —CONHR′, —CONRR′ wherein R and R′ represent (C₁-C₃)alkyl or Y—R₉;-   Y represents —O—, —S—, —S(O)—, —S(O)₂—, —NR_(a)—,    —NR_(a)C(O)NR_(b)—, —NR_(a)C(O)—, —C(O)NR_(a)—, —C(O)—, —C(O)O—,    —OC(O)—, —NR_(a)C(O)O—, —OC(O)NR_(a)—, —S(O)₂NR_(a)—, —NR_(a)S(O)₂—,    —OC(O)O— or —O(CH₂CH₂O)_(n)— wherein n is an integer between 1 and    6, and R_(a) and R_(b) independently represents hydrogen or    (C₁-C₃)alkyl;-   R₉ represents (C₁-C₆ )alkyl, (C₂-C₆)olefinic group, (C₃-C₆)cyclic    hydrocarbon group, heterocyclyl, (C₂-C₆)alkynyl,    (C₁-C₆)alkyl-(C₃-C₆)cyclic hydrocarbon or (C₁-C₆)alkyl-heterocyclyl,    and wherein R₉ may optionally be substituted by one or more    substituents represented by R₁₀;-   R₁₀ represents halogen, hydroxy, mercapto, trifluoromethyl, amino,    (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylamino or    (C₁-C₆)alkoxycarbonyl;-   and pharmaceutically acceptable salts, solvates and hydrates    thereof.

The invention also relates to compounds of formula I for use in therapy,and in particular to pharmaceutical compositions comprising a compoundof formula I.

In a further embodiment, the invention relates to methods of treatment,the methods comprising administering to a patient in need thereof aneffective amount of a compound of formula I.

In a yet further embodiment, the invention relates to the use ofcompounds of formula I in the manufacture of medicaments.

The compounds of formula I are prodrugs, as disclosed in WO 91/10639, inthe sense that the moiety attached to the N-atom, i.e.

is cleaved, probably enzymatically, from the aminobenzophenone core oncethe compound has penetrated into the skin. In this way, the active,potentially colour generating compound is only formed when it is insidethe skin, protected from light. The potentially colour generatingcompound is not exposed to light, and will therefore not give rise to adiscolouration of the skin, while the active compound is still deliveredto the affected part of the skin.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula I may comprise chiral carbon atoms andcarbon-carbon double bonds which may give rise to the existence ofisomeric forms, e.g. enantiomers, diastereomers and geometric isomers.The present invention relates to all such isomers, either in pure formor as mixtures thereof. Pure stereoisomeric forms of the compounds andthe intermediates of this invention may be obtained by the applicationof art-known procedures. Diastereomers may be separated by physicalseparation methods such as selective crystallization and chromatographictechniques, e. g. liquid chromatography using chiral stationary phases.Enantiomers may be separated from each other by the selectivecrystallization of their diastereomeric salts with optically activeacids. Alternatively, enantiomers may be separated by chromatographictechniques using chiral stationary phases. Said pure stereoisomericforms may also be derived from the corresponding pure stereoisomericforms of the appropriate starting materials, provided that the reactionoccurs stereoselectively or stereospecifically. Preferably, if aspecific stereoisomer is desired, said compound will be synthesized bystereoselective or stereospecific methods of preparation. These methodswill advantageously employ chirally pure starting materials. Likewise,pure geometric isomers may be obtained from the corresponding puregeometric isomers of the appropriate starting materials. A mixture ofgeometric isomers will typically exhibit different physical properties,and they may thus be separated by standard chromatographic techniqueswell-known in the art.

The term “pharmaceutically acceptable salt” is intended to indicatesalts prepared by reacting a compound of formula I with a suitableinorganic or organic acid, e.g. hydrochloric, hydrobromic, hydroiodic,sulfuric, nitric, acetic, phosphoric, lactic, maleic, phthalic, citric,propionic, benzoic, glutaric, gluconic, methanesulfonic, salicylic,succinic, tartaric, toluenesulfonic, sulfamic or fumaric acid.Pharmaceutically acceptable salts of compounds of formula I may also beprepared by reaction with a suitable base such as sodium hydroxide,potassium hydroxide, ammonia or the like.

The term “solvate” is intended to indicate a species formed byinteraction between a compound, e.g. a compound of formula I, and asolvent, e.g. alcohol, glycerol and water, wherein said species are in asolid form. When water is the solvent, said species is referred to as ahydrate.

The term “halogen” is intended to indicate members of the seventh maingroup of the periodic table, i.e. fluoro, chloro, bromo and iodo.

The term “alkyl” is intended to indicate a univalent radical derivedfrom a straight or branched alkane by removal of a hydrogen atom fromany carbon atom, and it includes the subclasses of primary, secondaryand tertiary alkyl groups, including for example (C₁-C₁₈)alkyl,(C₁-C₆)alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, pentyl, hexyl, heptyl, decanyl, etc.

The term “olefinic group” is intended to indicate a straight or branchedhydrocarbon radical having one or more carbon-carbon double bonds ofeither E or Z stereochemistry where applicable. The term includes, forexample, (C₂-C₁₈)olefinic group, (C₂-C₆)olefinic group and (C₂-C₃)olefinic group, vinyl, allyl, 1-butenyl, 2-butenyl, and2-methyl-2-propenyl, 2,4-pentenedienyl, etc.

The term “alkoxy” is intended to indicate a radical of the formula —OR,where R is alkyl as defined above, for example (C₁-C₁₈)alkoxy,(C₁-C₆)alkoxy, methoxy, ethoxy, n-propoxy, tert-butoxy, etc.

The term “alkylthio” is intended to indicate a radical of the formula—SR, where R is alkyl as defined above, for example (C₁-C₁₈)alkylthio,(C₁-C₆)alkylthio, methylthio, ethylthio, n-propylthio, 2-propylthio,etc.

The term “alkylamino” is intended to indicate a radical of the formula—NHR or —NR₂, where each R is alkyl as defined above and includes, forexample, methylamino, dimethylamino, di-(n-propyl)amino,n-butyl(ethyl)amino, etc.

The term “alkoxycarbonyl” is intended to indicate a radical of theformula —COOR, where R is alkyl as defined above and includesmethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl,etc.

The term “cyclic hydrocarbon group” includes saturated and unsaturated,optionally fused bicyclic, hydrocarbon rings, such as (C₃-C₈)cycloalkyl,cyclopropyl, cyclopentyl, cyclohexyl, and cyclooctyl, (C₃-C₈)cycloalkenegroup, cycloprop-2-enyl, cyclobut-2-enyl, cyclopent-2-enyl,cyclohex-3-enyl, cycloocta-4-enyl, cyclohex-3,5-dienyl and phenyl.

The term “cyclic hydrocarbon group” also includes compounds as justdefined wherein one or more ring —CH₂— fragments have been replaced by a—C(O)— fragment and /or an exo-cyclic carbon-carbon double bond, such asoxocyclohexyl, oxocyclopentyl, 4-oxo-1,2,3,4-tetrahydronaphtalen-1-yl,1-oxo-1,2,3,4-tetrahydronaphtalen-1-yl, 2-oxocyclohex-3-en-1-yl and2-oxocyclohex-1-en-1-yl, and

The term “alkynyl” is intended to indicate univalent group derived froma straight or branched alkyne by removal of a hydrogen atom from anycarbon atom, and includes the subclasses of primary, secondary andtertiary alkyl groups respectively, and having the number of carbonatoms specified, including for example (C₁-C₁₈)alkynyl, (C₂-C₆)alkynyl,ethynyl, propynyl, 1,1-dimethyl-3-butynyl, etc.

The term “heterocyclyl” is intended to indicate saturated orunsaturated, optionally fused carbocyclic rings comprising one or moreheteroatoms selected from the group consisting of O, N and S, such aspyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl,pyrazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, tetrahydrotiophenyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, putinyl, quinolinyl,isoquinolinyl, 1,2-dihydroquinolinyl, etc. The term “heterocyclyl” alsoincludes compounds as just defined wherein one or more ring —CH₂—fragments have been replaced by a —C(O)— fragment and/or an exo-cycliccarbon-carbon double bond, such as dioxopiperidinyl,1-oxo-3,4-dihydroisoquinolin-2(1H)-yl and

In a preferred embodiment, R₁ represents fluoro, chloro or bromo, methylor methoxy, and particularly preferred in this embodiment, R₁ representsmethyl.

In a preferred embodiment, R₂ represents on or more substituentsselected from the Ist consisting of hydrogen, fluoro, chloro, methyl ormethoxy, and particularly preferred in this embodiment, R₂ represents2-chloro.

In a preferred embodiment, R₃ represents one or more substituentsselected from the list consisting of hydrogen, fluoro, chloro, methyl,ethyl, ethenyl or methoxy, and particularly preferred in thisembodiment, R₃ represents 2-methyl and 4-fluoro, or 2-methyl and4-bromo.

In a preferred embodiment, R₄ represents one or more substituentsselected from the list consisting of hydrogen, fluoro, chloro, bromo,methyl and methoxy, and particularly preferred in this embodiment, R₄represents hydrogen or 4-chloro.

In a preferred embodiment, R₅ and R₆ each independently representhydrogen or (C₁-C₆)alkyl, such as (C₁-C₄)alkyl, such as methyl.

In a preferred embodiment, R₇ represents (C₁-C₁₀)alkyl, (C₃-C₆)cyclichydrocarbon group, (C₂-C₁₀)olefinic group, heterocyclyl,(C₂-C₁₀)alkynyl, (C₁-C₁₀)alkyl-heterocyclyl, (C₁-C₁₀)alkyl-(C₃-C₆)cyclichydrocarbon group, (C₂-C₁₀)olefinic group-heterocyclyl, (C₂-C₁₀),olefinic group-(C₃-C₆)cyclic hydrocarbon group,(C₂-C₁₀)alkynyl-heterocyclyl, (C₂-C₁₀)alkynyl-(C₃-C₆)cyclic hydrocarbongroup; and wherein R₇ may optionally be substituted by one or moresubstituents represented by R₈.

In a more preferred embodiment, R₇ represents (C₁-C₆)alkyl,(C₃-C₆)cyclic hydrocarbon group, (C₂-C₆)olefinic group, heterocyclyl,(C₂-C₆)alkynyl, (C₁-C₆)alkyl-heterocyclyl, (C₁-C₆)alkyl-(C₃-C₆)cyclichydrocarbon group, (C₂-C₆)olefinic group-heterocyclyl, (C₂-C₆), olefinicgroup-(C₃-C₆)cyclic hydrocarbon group, (C₂-C₆)alkynyl-heterocyclyl,(C₂-C₆)alkynyl-(C₃-C₆)cyclic hydrocarbon group; and wherein R₇ mayoptionally be substituted by one or more substituents represented by R₈.

In particular, R₇ represents methyl, ethyl, propyl, iso-propyl, butyl,tert-butyl, pentyl, heptyl, nonyl, 2-methyl-propyl, 1-methyl-propyl,2,2-dimethyl-propyl, cyclopropyl, cyclobutyl, phenyl, ethenyl, propenyl,phenylmethyl, phenyl-1-allyl or 2-, 3- or 4-pyridyl, all of which may besubstituted by R₈.

In a preferred embodiment, R₈ represents halogen, hydroxy,trifluoromethyl, amino, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonyl, (C₁-C₉)trialkylammonium in association with apharmaceutically acceptable anion, cyano, COOH or Y—R₉.

In a preferred embodiment, R₈ represents hydroxyl or carboxy.

In a preferred embodiment, Y represents —O—, —NR_(a)—, —NR_(a)C(O)—,—C(O)NR_(a)—, —C(O)—, —C(O)O—, —OC(O)—, —NR_(a)C(O)O— or—O(CH₂CH₂O)_(n)— wherein n is 1, 2, 3 or 4, and R_(a) and R_(b) bothrepresents hydrogen.

In a preferred embodiment, Y represents —C(O)—O—, NH—C(O)—O—, —O—,—O—C(O)— or — O(CH₂CH₂O)_(n)— wherein n is 3.

In a preferred embodiment, R₉ represents (C₁-C₄)alkyl, (C₂-C₃)olefinicgroup, (C₃-C₆)cyclic hydrocarbon group, heterocyclyl, (C₂-C₃)alkynyl,(C₁-C₃)alkyl-(C₃-C₆)cyclic hydrocarbon or (C₁-C₃)alkyl-heterocyclyl,wherein R₉ may optionally be substituted by one or more substituentsrepresented by R₁₀.

In a preferred embodiment, R₉ represents (C₁-C₄)alkyl or(C₁-C₃)alkyl-(C₃-C₆)cyclic hydrocarbon, and particularly preferred inthis embodiment, R₉ represents methyl, ethyl, tert-butyl orphenylmethyl.

In a preferred embodiment, R₁₀ represents fluoro, chloro, hydroxy,trifluoromethyl, amino, (C₁-C₃)alkyl, (C₁-C₃ )alkoxy, (C₁-C₃)alkylaminoor (C₁-C₃)alkoxycarbonyl.

Another preferred embodiment of the present invention relates tocompounds of formula I wherein R₁ is methyl; R₂ is 2-chloro; R₃ is2-methyl and 4-fluoro, or 2-methyl and 4-bromo; R₄ is hydrogen or4-chloro;

-   R₅ and R₆ independently represent hydrogen or (C₁-C₄)alkyl;-   R₇ represents (C₁-C₁₀)alkyl, (C₃-C₆)cyclic hydrocarbon group,    (C₂-C₁₀)olefinic group, heterocyclyl, (C₂-C₁₀)alkynyl,    (C₁-C₁₀)alkyl-heterocyclyl, (C₁-C₁₀)alkyl-(C₃-C₆)cyclic hydrocarbon    group, (C₂-C₁₀)olefinic group-heterocyclyl, (C₂-C₁₀), olefinic    group-(C₃-C₆)cyclic hydrocarbon group, (C₂-C₁₀)alkynyl-heterocyclyl,    (C₂-C₁₀)alkynyl-(C₃-C₆)cyclic hydrocarbon group; and wherein R₇ may    optionally be substituted by one or more substituents represented by    R₈;-   R₈ represents halogen, hydroxy, trifluoromethyl, amino,    (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino, (C₁-C₆    )alkoxycarbonyl, (C₁-C₉)trialkylammonium in association with a    pharmaceutically acceptable anion, cyano, —COOH or Y—R₉;-   Y represents —O—, —NR_(a)—, —NR_(a)C(O)—, —C(O)NR_(a)—, —C(O)—,    —C(O)O—, —OC(O)—, —NR_(a)C(O)O— or —O(CH₂CH₂O)_(n)— wherein n is 1,    2, 3 or 4, and R_(a) and R_(b) both represents hydrogen;-   R₉ represents (C₁-C₃)alkyl, (C₂-C₃)olefinic group, (C₃-C₆)cyclic    hydrocarbon group, heterocyclyl, (C₂-C₃)alkynyl,    (C₁-C₃)alkyl-(C₃-C₆)cyclic hydrocarbon or (C₁-C₃)alkyl-heterocyclyl,    wherein R₉ may optionally be substituted by one or more substituents    represented by R₁₀;-   R₁₀ represents fluoro, chloro, hydroxy, trifluoromethyl, amino,    (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylamino or    (C₁-C₃)alkoxycarbonyl;-   and pharmaceutically acceptable salts solvates or hydrates thereof.

Still another preferred embodiment of the present invention relates tocompounds of formula I wherein R₁ is methyl; R₂ is 2-chloro; R₃ is2-methyl and 4-fluoro, or 2-methyl and 4-bromo; R₄ is hydrogen or4-chloro;

-   R₅ and R₆ independently represent hydrogen or (C₁-C₄)alkyl;-   R₇ represents (C₁-C₆)alkyl, (C₃-C₆)cyclic hydrocarbon group,    (C₂-C₆)olefinic group, heterocyclyl, (C₂-C₆)alkynyl,    (C₁-C₆)alkyl-heterocyclyl, (C₁-C₆)alkyl-(C₃-C₆)cyclic hydrocarbon    group, (C₂-C₆)olefinic group-heterocyclyl, (C₂-C₆), olefinic    group-(C₃-C₆)cyclic hydrocarbon group, (C₂-C₆)alkynyl-heterocyclyl,    (C₂-C₆)alkynyl-(C₃-C₆)cyclic hydrocarbon group; and wherein R₇ may    optionally be substituted by one or more substituents represented by    R₈;-   R₈ represents halogen, hydroxy, trifluoromethyl, amino,    (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino,    (C₁-C₆)alkoxycarbonyl, (C₁-C₉)trialkylammonium in association with a    pharmaceutically acceptable anion, cyano, —COOH or Y—R₉;-   Y represents —O—, —NR_(a)—, —NR_(a)C(O)—, —C(O)NR_(a)—, —C(O)—,    —C(O)O—, —OC(O)—, —NR_(a)C(O)O— or —O(CH₂CH₂O)_(n)— wherein n is 1,    2, 3 or 4, and R_(a) and R_(b) both represents hydrogen;-   R₉ represents (C₁-C₃)alkyl, (C₂-C₃)olefinic group, (C₃-C₆)cyclic    hydrocarbon group, heterocyclyl, (C₂-C₃)alkynyl,    (C₁-C₃)alkyl-(C₃-C₆)cyclic hydrocarbon or (C₁-C₃)alkyl-heterocyclyl,    wherein R₉ may optionally be substituted by one or more substituents    represented by R₁₀;-   R₁₀ represents fluoro, chloro, hydroxy, trifluoromethyl, amino,    (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylamino or    (C₁-C₃)alkoxycarbonyl;-   and pharmaceutically acceptable salts solvates or hydrates thereof.

Yet another preferred embodiment of the present invention relates tocompounds of formula I wherein R₁ is methyl; R₂ is 2-chloro; R is2-methyl and 4-fluoro, or 2-methyl and 4-bromo; R₄ is hydrogen or4-chloro;

-   R₅ and R₆ independently represent hydrogen or methyl;-   R₇ represents methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl,    pentyl, heptyl, nonyl, 2-methyl-propyl, 1-methyl-propyl,    2,2-dimethyl-propyl, cyclopropyl, cyclobutyl, phenyl, ethenyl,    propenyl, phenylmethyl, phenyl-1-allyl or 2-, 3- or 4-pyridyl, all    of which may be substituted by R₈;-   R₈ represents hydroxyl, carboxy;-   Y represents —C(O)—O—, NH—C(O)—O, —O—, —O—C(O)— or    —O(CH₂—CH₂—O)_(n)—, n being 3;-   R₉ represents methyl, ethyl, tert-butyl or phenylmethyl;-   R₁₀ represents fluoro, chloro, hydroxy, trifluoromethyl, amino,    (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylamino or    (C₁-C₃)alkoxycarbonyl;-   and pharmaceutically acceptable salts, solvates and hydrates    thereof.

Specific examples of compounds of formula I include

-   Succinic acid benzyl ester    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Succinic acid    mono-{1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl}ester;-   Sodium    3-{1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethoxycarbonyl}-propionate;-   {2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   {2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid    1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethyl    ester;-   Succinic acid benzyl ester    1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethyl    ester;-   Succinic acid    mono-(1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethyl)    ester;-   Succinic acid    {(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-methyl    ester methyl ester;-   Succinic acid benzyl ester    {(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-methyl    ester;-   Acetic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Propionic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Butyric acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Butyric acid    [[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methyl    ester;-   Pentanoic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Hexanoic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Octanoic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Decanoic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Succinic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester ethyl ester;-   Methoxy-acetic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Methoxy-acetic acid    [[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methyl    ester;-   Butyric acid    1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   3-Methoxy-propionic acid    1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   3,3-Dimethyl-butyric acid    [[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methyl    ester;-   Cyclopropanecarboxylic acid    [[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methyl    ester;-   Cyclobutanecarboxylic acid    [[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methyl    ester;-   2-Hydroxy-propionic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   2-Methyl-but-2-enoic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   2-Hydroxy-2-methyl-propionic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   2-Hydroxy-2-methyl-propionic acid    1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Isobutyric acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Isobutyric acid    [[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methyl    ester;-   2,2-Dimethyl-propionic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   3-Methyl-butyric acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   2-Methyl-butyric acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Cyclopropanecarboxylic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Acrylic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   But-2-enoic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   But-2-enoic acid    [[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methyl    ester;-   Cyclobutanecarboxylic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   3-Methoxy-propionic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   2-Acetoxy-propionic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   2,2-Dimethyl-propionic acid    [[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methyl    ester;-   3-Phenyl-acrylic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Benzoic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Pyridine-2-carboxylic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Isonicotinic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Nicotinic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Nicotinic acid    1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   2-Hydroxy-benzoic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   Hydroxy-phenyl-acetic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester;-   (S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester (diastereomer A);-   (S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid    1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl    ester (diastereomer B).

The compounds of the present invention are prodrugs of compounds knownto be potent inhibitors of cytokines, such as IL-1β and TNF-α, possibledue to an inhibition of P38 MAP kinase. The compounds of the presentinvention are therefore believed to be useful in the treatment ofinflammatory diseases or states. In particular, the compounds may beuseful in the treatment amelioration or prevention of inflammatorydiseases or states of the skin, such as acne, atopic dermatitis, contactdermatitis and psoriasis. The compounds are also, as prodrugs of knowninhibitors of cytokines, believed to be useful in the treatment,amelioration or prevention of systemic inflammatory diseases or states,such as asthma, allergy, arthritis, rheumatoid arthritis,spondyloarthritis, gout, atherosclerosis, chronic inflammatory boweldisease, uveitis and septic shock. The present invention thereforeprovides a method of treating, ameliorating or preventing acne, atopicdermatitis, psoriasis, asthma, allergy, arthritis, rheumatoid arthritis,spondyloarthritis, gout, atherosclerosis, chronic inflammatory boweldisease, uveitis and septic shock, the method comprising administeringto a patient in need thereof an effective amount of a compound offormula I, optionally in combination with other therapeutically activecompounds.

The prodrug moiety may endow the compounds of the present invention withparticular advantages when used for the treatment of acne. The balancedhydrophilicity/hydrophobicity of said moiety may help targeting thecompounds to the hydrophobic environment of the comedones. For othertypes of therapeutic interventions involving compounds of the presentinvention, e.g. systemic administration, the prodrug moiety will helpthe compounds to achieve a proper solubility to optimise thebioavailability.

A patient is an animal, including mammalians, and particularly humans.Animals also include domestic animals, such as horses, cows, sheep,swine, poultry, fish, cats, dogs, and zoo animals.

The term “effective amount” is intended to indicate an amount whichgives rise to a therapeutic effect. The amount will vary, e.g. accordingto the age, size and sex of the patient, the disease and the severity ofsaid disease, and the effect which is desired to achieve. It lies withinthe capabilities of any skilled physician or veterinary to determinewhat an effective amount is in any given situation. Suitable examples of“effective amounts” are the administration of 0.1-200 mg/kg body weight,such as 0.5-50 mg/kg body weight one or more times daily.

In therapeutic interventions comprising administration of compounds ofthe present invention, other therapeutically active compounds normallyused in the treatment of the above indicated diseases may be used too.Such other therapeutically active compounds include glucocorticoids,vitamin D analogues, anti-histamines, platelet activating factor (PAF)antagonists, anticolinergic agents, methyl xanthines, β-adrenergicagents, COX-2 inhibitors, salicylates, indomethacin, flufenamate,naproxen, timegadine, gold salts, penicillamine, serumcholesterol-reducing agents, retinoids, zinc salts, andsalicylazosulfapyridin (Salazopyrin). Administration of saidtherapeutically active compound may be concomitantly or sequentially tothe administration of a compound of the present invention.

For use in therapy, compounds of the present invention may beneficiallybe presented in a pharmaceutical formulation. In a further aspect, theinvention relates to a pharmaceutical composition comprising a compoundof formula I, optionally together with another therapeutically activecompound, and one or more pharmaceutically acceptable carriers orexcipients. The carriers or excipients should be “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof the formulations and not deleterious to the recipient thereof.

Conveniently, the active ingredient comprises from 0.1-100% by weight ofthe formulation. Conveniently, unit dose of a formulation containbetween 50 mg and 5000 mg, preferably between 200 mg and 1000 mg of acompound of formula I.

By the term “unit dose” is meant a unitary, i.e. a single dose which iscapable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically and chemically stable unitdose comprising either the active material as such or a mixture of itwith solid or liquid pharmaceutical diluents or carriers.

The formulations include e.g. those in a form suitable for oral(including sustained or timed release), rectal, parenteral (includingsubcutaneous, intraperitoneal, intramuscular, intraarticular andintravenous), transdermal, ophthalmic, topical, nasal or buccaladministration.

The formulations may conveniently be presented in unit dose form and maybe prepared by any of the methods well known in the art of pharmacy,e.g. as disclosed in Remington, The Science and Practice of Pharmacy,20^(th) ed., 2000. All methods include the step of bringing the activeingredient into association with the carrier, which constitutes one ormore accessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units as capsules, sachets, tablets orlozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or non-aqueous liquid,such as ethanol or glycerol; or in the form of an oil-in-water emulsionor a water-in-oil emulsion. Such oils may be vegetable oils, such ase.g. cottonseed oil, sesame oil, coconut oil or peanut oil. Suitabledispersing or suspending agents for aqueous suspensions includesynthetic or natural gums such as tragacanth, alginate, acacia, dextran,sodium carboxymethylcellulose, gelatin, methylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers andpolyvinylpyrrolidone. The active ingredients may also be administered inthe form of a bolus, electuary or paste.

A tablet may be made by-compressing or moulding the active ingredientoptionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing, in a suitable machine, the activeingredient(s) in a free-flowing form such as a powder or granules,optionally mixed by a binder, such as e.g. lactose, glucose, starch,gelatine, acacia gum, tragacanth gum, sodium alginate,carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,polyethylene glycol, waxes or the like; a lubricant such as e.g. sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride or the like; a disintegrating agent such ase.g. starch, methylcellulose, agar, bentonite, croscarmellose sodium,sodium starch glycollate, crospovidone or the like or a dispersingagent, such as polysorbate 80. Moulded tablets may be made by moulding,in a suitable machine, a mixture of the powdered active ingredient andsuitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form ofsuppositories in which the compound of the present invention is admixedwith low melting water soluble or insoluble solids such as cocoa butter,hydrogenated vegetable oils, polyethylene glycol or fatty acids estersof polyethylene glycols, while elixirs may be prepared using myristylpalmitate.

Formulations suitable for parenteral administration convenientlycomprise a sterile oily or aqueous preparation of the activeingredients, which is preferably isotonic with the blood of therecipient, e.g. isotonic saline, isotonic glucose solution or buffersolution. The formulation may be conveniently sterilised by for instancefiltration through a bacteria retaining filter, addition of sterilisingagent to the formulation, irradiation of the formulation or heating ofthe formulation. Liposomal formulations as disclosed in e.g.Encyclopedia of Pharmaceutical Technology, vol. 9, 1994, are alsosuitable for parenteral administration.

Alternatively, the compound of formula I may be presented as a sterile,solid preparation, e.g. a freeze-dried powder, which is readilydissolved in a sterile solvent immediately prior to use.

Transdermal formulations may be in the form of a plaster or a patch.

Formulations suitable ophthalmic administration may be in the form of asterile aqueous preparation of the active ingredients, which may be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems e.g. as disclosed in Encyclopedia of PharmaceuticalTechnology, vol. 2, 1989, may also be used to present the activeingredient for ophthalmic administration.

Formulations suitable for topical or ophthalmic administration includeliquid or semi-liquid preparations such as liniments, lotions, gels,applicants, oil-in-water or water-in-oil emulsions such as creams,ointments or pastes; or solutions or suspensions such as drops.Particularly suited dermal formulations are disclosed in WO 02/45752,example 1, test formulations A-M, the teaching of which is incorporatedby reference herein in its entirety.

Formulations suitable for nasal or buccal administration include powder,self-propelling and spray formulations, such as aerosols and atomisers.Such formulations are disclosed in greater detail in e.g. ModernPharmaceutics, 2^(nd) ed., G. S. Banker and C. T. Rhodes (Eds.), page427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3^(th) ed., G.S. Banker and C. T. Rhodes (Eds.), page 618-619 and 718-721, MarcelDekker, New York and Encyclopedia of Pharmaceutical Technology vol. 10,J Swarbrick and J. C. Boylan (Eds), page 191-221, Marcel Dekker, NewYork.

Active transport forms of the present invention may also be delivered byuse of monoclonale antibodies as individual carriers to which thecompound molecules are coupled.

In addition to the aforementioned ingredients, the formulations of acompound of formula I may include one or more additional ingredientssuch as diluents, buffers, flavouring agents, colourant, surface activeagents, thickeners, preservatives, e.g. methyl hydroxybenzoate(including anti-oxidants), emulsifying agents and the like.

Said other therapeutically active compounds include glucocorticoids,vitamin D analogues, anti-histamines, platelet activating factor (PAF)antagonists, anticolinergic agents, methyl xanthines, β-adrenergicagents, COX-2 inhibitors, salicylates, indomethacin, flufenamate,naproxen, timegadine, gold salts, penicillamine, serumcholesterol-reducing agents, retinoids, zinc salts, andsalicylazosulfapyridin (Salazopyrin)

In still another embodiment, the invention relates to the use ofcompounds of formula I in the preparation of medicaments for use in thetreatment of acne, atopic dermatitis, contact dermatitis, psoriasis,asthma, allergy, arthritis, rheumatoid arthritis, spondyloarthritis,gout, atherosclerosis, chronic inflammatory bowel disease, uveitis andseptic shock.

Discolouring of Compounds of the Present Invention

The discolouring of compounds of formula I was investigated in acomparison with known aminobenzophenones.

Compounds were dissolved in DMSO at 100 mM. The solutions were diluted1:10 in the test vehicle (Ethanol:Labrasol:water 65:25:10) just prior tothe experiment. 10 ul aliquots were placed in droplets on filter paperand allowed to dry for 15 minutes into spots. Then the colour of thespots was scored using the following scale: Score 0: No colour 1: Veryfaint colour 2: Light colour 3: Medium colour 4: Strong colour

The spots were illuminated in a sun-test cabinet (Heraeus Suntest CPS)set for outdoor illumination for 5 minutes. The scoring was repeatedafter illumination. The results are shown in Table 1. TABLE 1 Colourscores Colour score prior Colour score after Compound to illuminationillumination Reference a 0 3 Reference b 1 3 Reference c 1 3 Compound112 0 0 Compound 113 0 0 Compound 133 0 0 Compound 147 0 0 Compound 1190 0Reference a:2-chloro-4-(4-fluoro-2-methyl-phenylamino)-2′-methylbenzophenone,compound 116 in WO 01/42189.Reference b:4-(2-amino-4-bromo-phenylamino)-2-chloro-2′-methylbenzophenone, compound101 in WO 01/05744Reference c: 4-(2-aminophenylamino)-2-chloro-2′-methylaminobenzophenon,compound 106 in WO 98/32730.

The above results clearly show that compounds of formula I have asignificantly decreased, or even totally absent, discolouration whenexposed to light. This property makes the compounds particular useful asmedicament for treatment of dermal diseases.

Biological Activity

Inhibition of Cytokine Production

To study the effect of the compound of the present invention in vitrothe inhibition of the IL-1β and TNF-α secretion was measured using thefollowing procedure:

Cytokine production was measured in the media from lipopolysaccharide(LPS) stimulated peripheral blood mononuclear cells. The mononuclearcells were isolated from human peripheral blood by Lymphoprep® (Nycomed,Norway) fractionation and suspended in RPMI 1640 (growth medium) withfoetal calf serum (FCS, 2%), at a concentration of 5×105 cells/ml. Thecells were incubated in 24-well tissue culture plates in 1 ml aliquots.Test compounds were dissolved in dimethylsulfoxide (DMSO, 10 mM) andwere diluted with the medium. Compounds were added to the cells for 30minutes, then LPS (1 mg/ml final concentration) was added. The plateswere incubated for 18 hours, and the concentration of IL-1β and TNF-α inthe medium was determined by enzyme-linked immunosorbent assays. Themedian inhibitory concentrations (IC₅₀) of the compounds werecalculated. The results are shown in Table 2. TABLE 2 Inhibition ofcytokines production in vitro by compounds of formula I The medianinhibition concentration (IC₅₀, nM) IL-1β TNF-α Reference a 32 7.9compound 112 25 12 compound 113 50 10 compound 133 79 20 compound 1377.9 5.0 compound 128 10 7.9Reference a:2-chloro-4-(4-fluoro-2-methyl-phenylamino)-2′-methylbenzophenone,compound 116 in WO 01/42189.

These results show that compounds of the present invention are able toinhibit the production of IL-1β and TNF-α, and showing a pharmacologicalactivity comparable to the reference compounds, thus making thempotentially useful in the treatment of inflammatory diseases.

Rhino Mouse Model

The rhino mouse is an in vivo model for the study of hyperplastic andcomedolytic potency of compounds used in the treatment of acne. Therhino mouse has follicles on the skin, the orifices of which aredistended with horny material, and these structures resembles humancomedones.

The model uses mouse of the strain RHJ/LeJ Rhino, hr^(rh)/hr^(rh). Themice are treated topically on the back daily for 21 days with the testcompound. Compounds are tested for their ability to reduce the number ofcomedones.

The number of comedones in the skin of the mouse is determined byhistological examination. The percentage change in the number ofcomedones compared to an untreated control group is calculated. Thecompounds were applied at 45 mM dissolved in acetone. Table 3 gives theresults TABLE 3 Reduction in number of comedones Reduction in numberCompound of comedones Compound 112 −56% Compound 113 −72% Compound 133−61%

The above data clearly show that compound of the present invention arecapable of reducing the number of comedones, and thus useful in thetreatment of acne.

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesised using the methodsoutlined below, together with methods known in the art of syntheticorganic chemistry, or variations thereof as appreciated by those skilledin the art. Preferred methods include, but are not limited to, thosedescribed below.

The compounds of formula I may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents that are appropriate with respect to the reagents and materialsemployed and that are suitable for the transformations being effected.Also, in the synthetic methods described below, it is to be understoodthat all proposed reaction conditions, including choice of solvent,reaction atmosphere, reaction temperature, duration of experiment andwork-up procedures, are chosen to be conditions of standard for thatreaction, which should be readily recognised by one skilled in the art.It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the educt molecule must becompatible with the reagents and reactions proposed. Not all compoundsof formula I falling into a given class may be compatible with some ofthe reaction conditions required in some of the methods described. Suchrestrictions to the substituents which are compatible with the reactionconditions will be readily apparent to one skilled in the art andalternative methods can be used.

Compounds according to the present invention may be prepared by aprocess comprising coupling of a chloride of the formula III with acarboxylate of the formula II, as shown on scheme 1, or alternatively bya process comprising coupling of a diaraylamine of the formula V with acabonchloridate with the formula VI, as shown on scheme 1, where R₁, R₂,R₃, R₄, R₅, R₆ and R₇ are as defined above, except that any substituentsor functional groups which are potentially reactive in the couplingreactions may themselves be protected before the coupling reactions areperformed and removed subsequently. The coupling reactions are typicallyperformed at room temperature or below (−20 to 40 C.°) in an inertsolvents like toluene, benzene, 1,4-dioxane, THF, diethyl ether anddichloromethane under an inert atmosphere, e.g argon or nitrogen.

Compounds according to the present invention may in special cases beprepared by a simple functional group interconversion (FGI), meaning astandard process, known to those skilled in the art of organicsynthesis, where a functional group in compounds with the generalformula I is transformed into a different functional group in one ormore synthetic steps, leading to a new compound with the general formulaI. Examples of such processes include, but are not limited to,hydrolysis of an ester to give an acid under basic conditions,deprotection of a tetrahydropyranylether to give an alcohol by treatmentwith e.g. a catalytic amount of acid, deprotection of a benzylic esterto give a carboxylic acid by catalytic hydrogenation and catalytichydrogenation of an olefin to give a saturated hydrocarbon.

Compounds according to the general formulas IV and VI may be prepared asdescribed in the literature (Folkmann, M., Lund, F. J.; Synthesis 1990,1159), which is hereby incorporated as reference.

Compounds according to the general formula V may be prepared by themethods disclosed in WO 01/42189, which is hereby incorporated byreference in its entirety.

EXAMPLES AND PREPARATIONS

The exemplified compounds are listed in Table 4.

All melting points are uncorrected. For ¹H nuclear magnetic resonance(NMR) spectra (300 MHz) and ¹³C NMR (75.6 MHz) chemical shift values (δ)(in ppm) are quoted, unless otherwise specified, for deuteriochloroformsolutions relative to internal tetramethylsilane (δ=0.00) or chloroform(δ=7.25) or deuteriochloroform (δ=76.81 for ¹³C NMR) standard. The valueof a multiplet, either defined (doublet (d), triplet (t), quartet (q))or not (m) at the approximate mid point is given unless a range isquoted. The organic solvents used were anhydrous. Chromatography wasperformed on silica gel using the flash technique.

The following abbreviations have been used throughout: DCMDichloromethane DMF N,N-Dimethylformamide MS Mass spectroscopy NMRNuclear magnetic resonance RT Room temperature THF Tetrahydrofuran

The numbering in Table 4 refers to the numbering in the formula below

TABLE 4 Exemplified compounds with the general formula I. (R₁ = methyl;R₂ = 2-Cl; R₃ = 2-CH₃, 4-F; R₄, and R₅ = H; unless otherwise noted).Example Compound no. R₆ R₇ 101 1 —CH₃ —CH₂CH₂COOBn 102 2 —CH₃—CH₂CH₂COOH 103 3 —CH₃ —CH₂CH₂COONa 104 4 —CH₃ —CH₂(OCH₂CH₂)₃OCH₃ 105 5—CH₃ —CH₂(OCH₂CH₂)₃OCH₃ R₃ = 2-CH₃, 4-Br 106 6 —CH₃ —CH₂CH₂COOBn R₃ =2-CH₃, 4-Br 107 7 —CH₃ —CH₂CH₂COOH R₃ = 2-CH₃, 4-Br 108 8 —H—CH₂CH₂COOCH₃ R₃ = 2-CH₃, 4-Br 109 9 —H —CH₂CH₂COOBn R₃ = 2-CH₃, 4-Br110 10 —CH₃ —CH₃ 111 11 —CH₃ —CH₂CH₃ 112 12 —CH₃ —CH₂CH₂CH₃ 113 13 —H—CH₂CH₂CH₃ 114 14 —CH₃ —CH₂CH₂CH₂CH₃ 115 15 —CH₃ —CH₂CH₂CH₂CH₂CH₃ 116 16—CH₃ —CH₂CH₂CH₂CH₂CH₃CH₂CH₃ 117 17 —CH₃ —CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₃ 11818 —CH₃ —CH₂CH₂COOCH₂CH₃ 119 19 —CH₃ —CH₂OCH₃ 120 20 —H —CH₂OCH₃ 121 21—CH₃ —CH₂CH₂CH₃ R₄ = 4-Cl 122 22 —CH₃ —CH₂CH₂OCH₃ R₄ = 4-Cl 123 23 —H

124 24 —H

125 25 —H

126 26 —CH₃

127 27 —CH₃

128 28 —CH₃

129 29 —CH₃

R₄ = 4-Cl 130 30 —CH₃

131 31 —H

132 32 —CH₃

133 33 —CH₃

134 34 —CH₃

135 35 —CH₃

136 36 —CH₃

137 37 —CH₃

138 38 —H

139 39 —CH₃

140 40 —CH₃

141 41 —CH₃

142 42 —H

143 43 —CH₃

144 44 —CH₃

145 45 —CH₃

146 46 —CH₃

147 47 —CH₃

148 48 —CH₃

R₄ = 4-Cl 149 49 —CH₃

150 50 —CH₃

151 51 —CH₃

diastereomer A 152 52 —CH₃

diastereomer B

Preparation 1:[3-Chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamicacid 1-chloro-ethyl ester (compound 301)

The reaction was conducted under an atmosphere of argon. Sodium hydride(814 mg, 34 mmol) was added in small portions to a solution of[2-chloro-4-(4-fluoro-2-methyl-phenylamino)-phenyl]-o-tolyl-methanone(2.00 g, 5.65 mmol)( disclosed in WO 01/42189) in DMF (10 mL) at 0° C.under stirring. 1-Chloroethyl chloroformate (1.62 g, 11.3 mmol) wasadded and the reaction mixture was allowed to come to RT overnight.After 18 h at RT the mixture was poured into a mixture of saturatedNH₄Cl (aq.) and EtOAc. The aqueous phase was extracted with more EtOAc(×2). The combined organic phases were washed with water, brine, dried(MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography using EtOAc/petroleum ether 1:8 as theeluent to afford the title compound as yellow oil.

Preparation 2:(4-Bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamicacid 1-chloro-ethyl ester (compound 302)

The reaction was conducted under an atmosphere of argon. Sodium hydride(1.04 g, 43 mmol) was added in small portions to a solution of[4-(4-bromo-2-methyl-phenylamino)-2-chloro-phenyl]-o-tolyl-methanone(3.0 g, 7.23 mmol)( disclosed in WO 01/42189) in DMF (25 mL) at 0° C.under stirring. 1-Chloroethyl chloroformate (2.07 g, 14.4 mmol) wasadded and the reaction mixture was allowed to come to RT overnight.After 18 h at RT the mixture was poured into a mixture of saturatedNH₄Cl (aq.) and EtOAc. The aqueous phase was extracted with more EtOAc(×2). The combined organic phases were washed with water, brine, dried(MgSO₄), filtered and concentrated in vacuo to give the title compound.The crude product was used immediately without any further purification.

Preparation 3: Succinic acid ethylsulfanylcarbonyloxymethyl ester methylester (compound 303)

A mixture of thiocarbonic acid S-ethyl ester O-iodomethyl ester (2.5 g,10 mmol) (Synthesis 1990, 1159-1166) and potassium 3-methoxycarbonylpropionate (2.55 g, 15 mmol) in DMF (20 mL) was stirred overnight at RT.The reaction mixture was poured into a mixture of ice/water and diethylether. The aqueous phase was extracted with more diethyl ether. Thecombined organic phases were washed with 5% NaHCO₃, water, dried(MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography using diethyl ether/petroleum ether 1:1as the eluent to afford the title compound as oil.

Preparation 4: Succinic acid chlorocarbonyloxymethyl ester methyl ester(compound 304)

A solution of compound 303 (580 mg, 2.3 mmol) in redistilledsulphonylchloride (0.20 mL, 2.5 mmol) was stirred at 0° C. for 15 minand then at RT for 2 h. The reaction mixture was concentrated in vacuoand then co-evaporated with toluene (×2) to give the title compound asoil, which is only stable in solution (5.0 mL diethyl ether).

Preparation 5: Succinic acid ethylsulfanylcarbonyloxymethyl ester benzylester (compound 305)

A solution of thiocarbonic acid S-ethyl ester O-iodomethyl ester (2.5 g,10 mmol) (Synthesis 1990, 1159-1166) and silver 3-benzyloxycarbonylpropionate (3.5 g, 11 mmol) in DCM (1.00 mL) was stirred for 72 h at RT.The reaction mixture was filtered and washed with DCM and concentratedin vacuo. The crude product was purified by flash chromatography usingdiethyl ether/petroleum ether 1:1 as the eluent to afford the titlecompound as colourless oil.

Preparation 6: Succinic acid chlorocarbonyloxymethyl ester benzyl ester(compound 306)

The reaction and work up was conducted as described in the preparationof compound 304. Starting compounds was compound 305 (1.00 g g, 3.0mmol). The title compound was dissolved in THF (3.0 mL).

Preparation 7:[3-Chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamicacid chloro-methyl ester (compound 307)

The reaction was conducted under an atmosphere of argon. A solution ofpotassium bis(trimethylsilyl)amide (34.77 mL, 0.5 M, 17.38 mmol) intoluene was added to a solution of[2-chloro-4-(4-fluoro-2-methyl-phenylamino)-phenyl]-o-tolyl-methanone(6.0 g, 17.0 mmol)( disclosed in WO 01/42189) in THF (170 mL) at −50° C.under stirring. After 15 min chloromethyl chloroformate (1.53 mL, 17.1mmol) was added and the reaction mixture was stirred at −50° C. for 60min and at RT for 60 min. The reaction mixture was washed with water,brine, dried (MgSO₄), filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography using diethylether/petroleum ether 2:1 as the eluent to afford the title compound.

Preparation 8:[3-Chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamicacid 1-chloro-ethyl ester (compound 308)

The reaction was conducted under an atmosphere of argon. A solution ofpotassium bis(trimethylsilyl)amide (8.6 mL, 0.5 M, 4.3 mmol) in toluenewas added to a solution of[2-chloro-4-(4-fluoro-2-methyl-phenylamino)-phenyl]-(4-chloro-2-methyl-phenyl)-methanone(1.55 g, 4.00 mmol)(prepared by the methods disclosed in WO 01/42189) inTHF (40 mL) at −50° C. under stirring. After 15 min 1-chloroethylchloroformate (0.5 mL, 4.6 mmol) was added and the reaction mixture wasstirred at −50° C. for 60 min and at RT for 60 min. The reaction mixturewas washed with water, brine, dried (MgSO₄), filtered and concentratedin vacuo. The crude product was purified by flash chromatography usingdiethyl ether/petroleum ether 2:1 as the eluent to afford the titlecompound.

Example 1 Succinic acid benzyl ester1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 101)

The reactions were conducted under an argon atmosphere. Sodium3-benzyloxycarbonyl-propionate (695 mg, 3.02 mmol) and tetrabutylamoniumhydrogensulphate (256 mg, 0.76 mmol) was added to a solution of compound301 (1.39 g, 3.02 mmol)) in DMF (10 mL) at 0° C. under stirring. Thereaction mixture was stirred for 20 days at 5° C. after which it waspoured into a mixture of water and EtOAc. The aqueous phase wasextracted with more EtOAc. The combined organic phases were washed withwater, brine, dried (MgSO₄), filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography using EtOAc/petroleumether 1:8 followed by 1:4 as the eluent to afford the title compound asfoam.

¹³C NMR (CDCl₃): δ 196.5, 171.7, 170.4, 162.1 (d), 151.9, 144.3, 139.2,137.2, 135.7, 135.5, 134.9 (d), 132.7, 131.9, 131.8, 131.0, 130.7,128.6, 128.3, 128.2, 125.5, 124.9, 121.3, 118.1 (d), 114.3 (d), 90.6,66.6, 28.9, 28.8, 21.0, 19.5, 17.8

Example 2 Succinic acidmono-{1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl}ester(compound 102)

A solution of compound 101 (637 mg, 1.01 mmol) in EtOAc (7.0 mL) wasadded Pd/C (84 mg, 10%) and then hydrogenated under an atmosphere ofhydrogen (1 atm.). After 5 h the reaction mixture was filtered throughDecalite. The crude product was purified by flash chromatography usingacetic acid/Et₂O/petroleum ether 0.02:1:1 as the eluent to afford thetitle compound as white solid.

¹³C NMR (CDCl₃): δ 196.7, 177.5, 170.3, 162.1 (d), 151.9, 144.3, 139.2,138.7, 137.2, 135.5, 134.9 (d), 132.6, 131.9, 131.8, 131.0, 130.7,125.5, 124.9, 121.4, 118.1 (d), 114.3 (d), 90.7, 28.7, 28.5, 21.0, 19.5,17.8

Example 3 Sodium3-{1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethoxycarbonyl}-propionate(compound 103)

A solution of compound 102 (220 mg, 0.40 mmol) in acetone (1.5 mL) wasmixed with a solution of sodium hydroxide (0.40 mL, 1.0 M, Aq.) inacetone (5.0 mL). The resulting solution was concentrated in vacuo anddried for 4 h in a freeze-dryer to give the title compound as whitesolid.

¹³C NMR (CDCl₃): δ 196.5, 171.8, 162.1 (d), 152.1, 144.2, 139.2, 137.1,135.6, 134.9 (d), 132.6, 131.9, 131.8, 131.0, 130.7, 125.6, 125.0,121.6, 118.0 (d), 114.3 (d), 90.6, 30.0, 29.7, 21.0, 19.4, 17.8

Example 4 {2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 104)

The reactions were conducted under an argon atmosphere. To a solution of{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid (434 mg, 1.95 mmol)in acetone (2.0 mL) was added tetrabutylammonium hydroxide (1.3 ml, 40%in water, 1.95 mmol) under stirring. After 10 min the reaction mixturewas concentrated in vacuo (oil pump). A solution of compound 301 (898mg, 1.95 mmol) in dry DMF (6.0 mL) was added to the residue. Thereaction mixture was stirred 14 days at 10° C. after which it was pouredinto a mixture of water and EtOAc. The aqueous phase was extracted withmore EtOAc. The combined organic phases were washed with water, brine,dried (MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography using EtOAc/petroleum ether 2:1 as theeluent to afford the title compound as yellow oil.

¹³C NMR (CDCl₃): δ 196.5, 168.7, 162.1 (d), 151.8, 144.2, 139.2, 138.7,137.2, 135.6, 134.8 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.8, 121.3, 118.1 (d), 114.3 (d), 90.7, 72.0, 71.0, 70.6, 70.5, 68.3,59.0, 21.0, 19.6, 17.9

Example 5 {2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethylester (compound 105)

The reaction and work up was conducted as described in the preparationof compound 104. Starting compounds were compound 302 (1.26 g g, 2.41mmol) and {2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid (536 mg,2.41 mmol). The crude product was purified by flash chromatography usingEt₂O/petroleum ether 1:2 as the eluent to afford the title compound.

¹³C NMR (CDCl₃): δ 196.5, 168.7, 151.5, 143.9, 139.3, 138.4, 138.0,137.1, 135.8, 134.4, 132.7, 131.9, 131.8, 131.0, 130.7, 130.6, 125.5,124.9, 122.4, 121.4, 90.7, 71.9, 71.0, 70.6, 70.5, 68.3, 59.0, 21.0,19.6, 17.6

Example 6 Succinic acid benzyl ester1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethylester (compound 106)

The reaction and work up was conducted as described in the preparationof compound 104. Starting compounds were compound 302 (2.51 g g, 4.82mmol) and sodium 3-benzyloxycarbonyl-propionate (1.11 g, 4.82 mmol). Thecrude product was purified by flash chromatography using Et₂O/petroleumether 1:4 as the eluent to afford the title compound as brown oil.

¹³C NMR (CDCl₃): δ 196.5, 171.7, 170.4, 151.7, 144.0, 139.3, 138.1,137.2, 135.7, 135.6, 134.4, 132.7, 131.9, 131.8, 131.0, 130.7, 130.6,128.6, 128.3, 128.2, 125.5, 125.0, 125.0, 122.4, 121.5, 90.6, 66.6,28.9, 28.8, 21.0, 19.5, 17.6

Example 7 Succinic acidmono-(1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethyl)ester (compound 107)

The reaction and work up was conducted as described in the preparationof compound 102. Starting compound was compound 106 (2.51 g g, 4.82mmol). The crude product was purified by flash chromatography usingEtOAc/petroleum ether 1:1 followed by EtOAc as the eluent to afford thetitle compound.

Example 8 Succinic acid{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-methylester methyl ester (compound 108)

The reaction was conducted under an argon atmosphere. To a stirredsolution of[4-(4-bromo-2-methyl-phenylamino)-2-chloro-phenyl]-o-tolyl-methanone(415 mg, 1.00 mmol)(disclosed in WO 01/42189) in THF (10 mL) at −50° C.was added potassium bis(trimethylsilyl)amide (2.0 mL, 0.5 M in toluene).After 15 min a solution of compound 304 (2.05 ml, 1 mmol) in diethylether was added and the solution was stirred at RT for 18 h. Thereaction mixture was poured into a mixture of ice-water and EtOAc. Theaqueous phase was extracted with more EtOAc. The combined organic phaseswere washed with water, brine, dried (MgSO₄), filtered and concentratedin vacuo. The crude product was purified by flash chromatography usingEtOAc/petroleum ether 1:1 as the eluent to afford the title compound asfoam.

¹H NMR (CDCl₃): δ 7.47 (m, 1H), 7.43-7.35 (m, 4H), 7.31 (dd, 1H), 7.29(m, 1H), 7.22-7.16 (m, 2H), 7.06 (d, 1H), 5.80 (s, 2H), 3.69 (s, 3H),2.71-2.61 (m, 4H), 2.53 (s, 3H), 2.16 (s, 3H)

Example 9 Succinic acid benzyl ester{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-methylester (compound 109)

The reaction and work up was conducted as described in the preparationof compound 108. Starting compounds were compounds[4-(4-bromo-2-methyl-phenylamino)-2-chloro-phenyl]-o-tolyl-methanone(830 mg, 2.00 mmol)(disclosed in WO 01/42189) and compound 306 (2.10 mL,2.1 mmol) The crude product was purified by flash chromatography usingEtOAc/petroleum ether 1:1 as the eluent to afford the title compound.

¹H NMR (CDCl₃): δ 7.46 (m, 1H), 7.43-7.25 (m, 11H), 7.21-7.14 (m, 2H),7.04 (d, 1H), 5.78 (s, 2H), 5.12 (s, 2H), 2.69 (s, 4H), 2.52 (s, 3H),2.14 (s, 3H)

Example 10 Acetic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 110)

To a solution of compound 301 (460 mg, 1.0 mmol) in THF (10.0 mL) wasadded tetrabutylammonium acetate (1.0 g, 3.3 mmol) under stirring. Thereaction mixture was stirred for 18 h at RT after which it was washedwith water, brine, dried (MgSO₄), filtered and concentrated in vacuo.The crude product was purified by flash chromatography using diethylether/petroleum ether 1:6 as the eluent to afford the title compound.

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.05-6.92 (m,2H), 6.86 (q, 1H), 2.52 (s, 3H), 2.18 (bs, 3H), 2.05 (s, 3H), 1.42 (d,3H)

Example 11 Propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 111)

To a solution of compound 301 (920 mg, 2.0 mmol) in THF (10.0 mL) wasadded tetrabutylammonium propionate (1.25 g, 4.0 mmol) under stirring.The reaction mixture was stirred for 18 h at RT after which it waswashed with water, brine, dried (MgSO₄), filtered and concentrated invacuo. The crude product was purified by flash chromatography usingdiethyl ether/petroleum ether 1:2 as the eluent to afford the titlecompound.

¹³C NMR (CDCl₃): δ 196.6, 172.5, 162.1 (d), 151.9, 144.3, 139.2, 138.8,137.2, 135.4, 134.9 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.8, 121.2, 118.0 (d), 114.2 (d), 90.4, 27.4, 21.0, 19.5, 17.8, 8.8

Example 12 Butyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 112)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (920mg, 2.0 mmol) and tetrabutylammonium butyrate (1.0 g, 3.0 mmol).

¹³C NMR (CDCl₃): δ 196.6, 171.7, 162.1 (d), 151.9, 144.3, 139.2, 138.7,137.2, 135.4, 134.9 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.8, 121.2, 118.0 (d), 114.2 (d), 90.4, 35.9, 21.0, 19.6, 18.2, 17.8,13.5

Example 13 Butyric acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester (compound 113)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 307 (450mg, 1.0 mmol) and tetrabutylammonium butyrate (495 mg, 1.5 mmol).

¹³C NMR (CDCl₃): δ 196.5, 172.0, 162.2 (d), 152.5, 144.1, 139.3, 138.6(d), 137.1, 135.7, 134.7 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 130.4(d), 125.5, 124.8, 121.2, 118.2 (d), 114.4 (d), 80.9, 35.8, 21.0, 18.1,17.8, 13.5

Example 14 Pentanoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 114)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (620mg, 1.5 mmol) and tetrabutylammonium pentanoate (855 mg, 2.5 mmol).

¹³C NMR (CDCl₃): δ 196.6, 171.8, 162.1 (d), 151.9, 144.3, 139.2, 138.7(d), 137.3, 135.4, 134.9 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.8, 121.2, 118.0 (d), 114.2 (d), 90.4, 33.8, 26.7, 22.1, 21.0, 19.6,17.8, 13.7

Example 15 Hexanoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 115)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (1.40g, 3.0 mmol) and tetrabutylammonium hexanoate (1.60 g, 4.47 mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.05-6.91 (m,2H), 6.86 (q, 1H), 2.52 (s, 3H), 2.28 (t, 2H), 2.17 (bs, 3H), 1.59 (m,2H), 1.43 (d, 3H), 1.37-1.20 (m, 4H), 0.89 (bt, 3H)

Example 16 Octanoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 116)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (1.0g, 2.2 mmol) and tetrabutylammonium octanoate (1.3 g, 3.4 mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.05-6.91 (m,2H), 6.86 (q, 1H), 2.52 (s, 3H), 2.28 (t, 2H), 2.17 (bs, 3H), 1.59 (m,2H), 1.43 (d, 3H), 1.36-1.20 (m, 8H), 0.88 (bt, 3H)

Example 17 Decanoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 117)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (1.40g, 3.0 mmol) and tetrabutylammonium decanoate (1.9 g, 4.5 mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.05-6.91 (m,2H), 6.86 (q, 1H), 2.52 (s, 3H), 2.28 (t, 2H), 2.17 (bs, 3H), 1.58 (m,2H), 1.43 (bd, 3H), 1.38-1.20 (m, 12H), 0.88 (bt, 3H)

Example 18 Succinic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester ethyl ester (compound 118)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (460mg, 1.00 mmol) and tetrabutylammonium 3-ethoxycarbonyl-propionate (600mg, 1.5 mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.05-6.93 (m,2H), 6.89 (q, 1H), 4.14 (q, 2H), 2.68-2.54 (m, 4H), 2.52 (s, 3H), 2.17(bs, 3H), 1.43 (d, 3H), 1.25 (t, 3H)

Example 19 Methoxy-acetic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 119)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (920mg, 2.0 mmol) and tetrabutylammonium 2-methoxy-acetate (1.0 g, 3.0mmol).

¹³C NMR (CDCl₃): δ 196.5, 168.5, 162.1 (d), 151.8, 144.1, 139.3, 138.6,137.1, 135.6, 134.8 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.9, 121.3, 118.1 (d), 114.3 (d), 90.7, 69.4, 59.4, 21.0, 19.5, 17.9

Example 20 Methoxy-acetic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 307 (1.44 mL, 1.39 Min THF, 2.0 mmol) and tetrabutylammonium 2-methoxy-acetate (995 mg, 3.0mmol). The crude product was purified by flash chromatography usingdiethyl ether/petroleum ether as a gradient from 1:2 to 2:1 as theeluent to afford the title compound.

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.23-7.10 (m, 3H), 7.06-6.93 (m,2H), 5.85 (bs, 2H), 4.08 (s, 2H), 3.45 (s, 3H), 2.53 (s, 3H), 2.17 (s,3H)

Example 21 Butyric acid1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 121)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 308 (495mg, 1.0 mmol) and tetrabutylammonium butyrate (500 mg, 1.5 mmol).

¹³C NMR (CDCl₃): δ 195.5, 171.7, 162.1 (d), 151.9, 144.6, 141.3, 138.8,137.9, 135.7, 135.0, 134.9 (d), 132.7, 132.3, 131.8, 130.6, 125.8,124.7, 121.2, 118.1 (d), 114.3 (d), 90.4, 35.9, 20.9, 19.6, 18.2, 17.8,13.5

Example 22 3-Methoxy-propionic acid1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 122)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 308 (495mg, 1.0 mmol) and tetrabutylammonium 3-methoxy-propionate (520 mg, 1.5mmol).

¹³C NMR (CDCl₃): δ 195.5, 169.7, 162.1 (d), 151.9, 144.6, 141.3, 138.9,137.9, 135.7, 135.0, 134.8 (d), 132.6, 132.3, 131.8, 130.6, 125.8,124.7, 121.3, 118.1 (d), 114.3 (d), 90.5, 67.5, 58.8, 34.8, 20.9, 19.5,17.8

Example 23 3,3-Dimethyl-butyric acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester (compound 123)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 307 (1.44 mL, 1.39 Min THF, 2.0 mmol) and tetrabutylammonium 2,2-dimethyl-propionate (1.12g, 3.0 mmol). The crude product was purified by flash chromatographyusing diethyl ether/petroleum ether as a gradient from 5:95 to 90:10 asthe eluent to afford the title compound.

¹³C NMR (CDCl₃): δ 196.5, 170.6, 162.2 (d), 152.5, 144.1, 139.3, 138.6(d), 137.1, 135.6, 134.7 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 130.5(d), 125.5, 124.8, 121.2, 118.2 (d), 114.4 (d), 80.9, 47.4, 30.8, 29.5,21.0, 17.8

Example 24 Cyclopropanecarboxylic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester (compound 124)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 307 (531mg, 1.19 mmol) and tetrabutylammonium cyclopropanecarboxylate (583 mg,1.78 mmol).

¹³C NMR (CDCl₃): δ 196.5, 173.4, 162.2 (d), 152.6, 144.2, 139.3, 138.6(d), 137.2, 135.7, 134.7 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 130.5(d), 125.5, 124.8, 121.2, 118.2 (d), 114.4 (d), 80.9, 21.0, 17.8, 12.6,9.1

Example 25 Cyclobutanecarboxylic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester (compound 125)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 307 (1.44 mL, 1.39 Min THF, 2.0 mmol) and tetrabutylammonium cyclobutanecarboxylate (1.02 g,3.0 mmol). The crude product was purified by flash chromatography usingdiethyl ether/petroleum ether as a gradient from 0:100 to 40:60 as theeluent to afford the title compound.

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.23-7.10 (m, 3H), 7.06-6.93 (m,2H), 5.78 (m, 2H), 3.17 (m, 1H), 2.53 (s, 3H), 2.37-2.10 (m, 4H), 2.16(s, 3H), 1.98 (m, 2H)

Example 26 2-Hydroxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 126)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 301 (920 mg, 2.0 mmol)and tetrabutylammonium 2-hydroxy-propionate (1.0 g, 3.0 mmol). The crudeproduct was purified by flash chromatography using diethylether/petroleum ether as a gradient from 1:2 to 2:1 as the eluent toafford the title compound.

¹³C NMR (CDCl₃): δ 196.5, 173.8, 162.2 (d), 151.8, 144.1, 139.3, 138.5,137.1, 135.7, 134.8 (d), 132.7, 132.0, 131.8, 131.0, 130.7, 130.5,125.5, 124.9, 121.3, 118.1 (d), 114.4 (d), 91.1, 66.6, 21.0, 20.1, 19.5,17.8

Example 27 (E)-2-Methyl-but-2-enoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 127)

The reaction and work up was conducted as described in the preparationof compound 111 except that the reaction was stopped after 3 h. Startingcompounds were compound 301 (920 mg, 2.0 mmol) and tetrabutylammonium(E)-2-methyl-but-2-enoate (1.03 g, 3.0 mmol). The crude product waspurified by flash chromatography using diethyl ether/petroleum ether asa gradient from 1:2 to 2:1 as the eluent to afford the title compound.

¹³C NMR (CDCl₃): δ 196.6, 165.9, 162.1 (d), 152.0, 144.4, 139.2, 139.0,138.7, 137.3, 135.4, 135.0 (d), 132.7, 131.9, 131.8, 131.0, 130.6,127.8, 125.5, 124.9, 121.3, 118.0 (d), 114.2 (d), 90.7, 21.0, 19.7,17.8, 14.5, 11.9

Example 28 2-Hydroxy-2-methyl-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 128)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (920mg, 2.0 mmol) and tetrabutylammonium 2-hydroxy-2-methyl-propionate (1.2g, 3.5 mmol).

¹³C NMR (CDCl₃): δ 196.5, 175.6, 162.1 (d), 151.7, 144.1, 139.3, 138.6(d), 137.1, 135.6, 134.7 (d), 132.7, 132.0, 131.8, 131.0, 130.7, 125.5,124.7, 121.2, 118.1 (d), 114.3 (d), 91.3, 71.9, 27.0, 26.8, 21.0, 19.4,17.8

Example 29 2-Hydroxy-2-methyl-propionic acid1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 129)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 308 (495 mg, 1.0 mmol)and tetrabutylammonium 2-hydroxy-2-methyl-propionate (550 mg, 1.6 mmol).The crude product was purified by flash chromatography using diethylether/petroleum ether 1:1 as the eluent to afford the title compound.

¹³C NMR (CDCl₃): δ 195.4, 175.6, 162.2 (d), 151.7, 144.3, 141.3, 138.7,138.0, 135.6, 135.2, 134.7, 132.7, 132.3, 131.8, 130.6, 130.5 (d),125.8, 124.7, 121.2, 118.1 (d), 114.4 (d), 91.3, 71.9, 27.0, 26.8, 20.9,19.4, 17.8

Example 30 Isobutyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 130)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (460mg, 1.00 mmol) and tetrabutylammonium 2-methyl-propionate (550 mg, 1.66mmol).

¹³C NMR (CDCl₃): δ 196.6, 175.1, 162.1 (d), 151.9, 144.3, 139.2, 138.7,137.2, 135.4, 135.0 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.7, 121.2, 118.0 (d), 114.2 (d), 90.4, 33.8, 21.0, 19.5, 18.8, 18.5,17.8

Example 31 Isobutyric acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester (compound 131)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 307 (540mg, 1.20 mmol) and tetrabutylammonium 2-methyl-propionate (760 mg, 2.30mmol).

¹³C NMR (CDCl₃): δ 196.5, 175.5, 162.2 (d), 152.5, 144.2, 139.3, 138.6(d), 137.2, 135.7, 134.7 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 130.5(d), 125.5, 124.8, 121.2, 118.2 (d), 114.4 (d), 81.0, 33.8, 21.0, 18.7,17.8

Example 32 2,2-Dimethyl-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 132)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (460mg, 1.00 mmol) and tetrabutylammonium 2,2-dimethyl-propionate (570 mg,1.66 mmol).

¹³C NMR (CDCl₃): δ 196.6, 176.5, 162.1 (d), 151.9, 144.4, 139.2, 138.8,137.3, 135.4, 135.0 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.7, 121.1, 118.0 (d), 114.2 (d), 90.6, 38.6, 26.8, 21.0, 19.4, 17.8

Example 33 3-Methyl-butyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 133)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (690mg, 1.50 mmol) and tetrabutylammonium 3-methyl-butanoate (860 mg, 2.50mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.04-6.91 (m,2H), 6.86 (q, 1H), 2.52 (s, 3H), 2.17 (bs, 3H), 2.16 (d, 2H), 2.07 (m,1H), 1.44 (d, 3H), 0.92 (d, 6H)

Example 34 2-Methyl-butyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 134)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (460mg, 1.00 mmol) and tetrabutylammonium 2-methyl-butanoate (570 mg, 1.66mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.04-6.90 (m,2H), 6.86 (q, 1H), 2.52 (s, 3H), 2.33 (m, 1H), 2.17 (bs, 3H), 1.74-1.34(m, 2H), 1.44 (bd, 3H), 1.14-1.07 (d, 3H), 0.91-0.79 (t, 3H)

Example 35 Cyclopropanecarboxylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 135)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (460mg, 1.00 mmol) and tetrabutylammonium cyclopropanecarboxylate (500 mg,1.50 mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.05-6.92 (m,2H), 6.86 (q, 1H), 2.52 (s, 3H), 2.17 (bs, 3H), 1.56 (m, 1H), 1.44 (bd,3H), 1.01 (m, 2H), 0.90 (m, 2H)

Example 36 Acrylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl ester (compound 136)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (460mg, 1.00 mmol) and tetrabutylammonium acrylate (520 mg, 1.66 mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-7.10 (m, 3H), 7.05-6.89 (m,3H), 6.46 (dd, 1H, J=17.2 Hz and 1.5 Hz), 6.08 (dd, 1H, J=17.2 Hz and10.3 Hz), 5.90 (dd, 1H, J=10.3 Hz and 1.5 Hz), 2.52 (s, 3H), 2.17 (bs,3H), 1.47 (bd, 3H)

Example 37 (E)-But-2-enoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 137)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (460mg, 1.00 mmol) and tetrabutylammonium (E)-but-3-enoate (500 mg, 1.50mmol).

¹H NMR (CDCl₃): δ 7.44-7.25 (m, 5H), 7.22-6.89 (m, 7H), 5.80 (dq, 1H,J=15.6 Hz and 1.6 Hz), 2.52 (s, 3H), 2.17 (bs, 3H), 1.89 (dd, 3H), 1.45(bd, 3H)

Example 38 (E)-But-2-enoic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester (compound 138)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 307 (446mg, 1.00 mmol) and tetrabutylammonium (E)-but-3-enoate (491 mg, 1.5mmol).

¹³C NMR (CDCl₃): δ 196.5, 164.6, 162.2 (d), 152.7, 147.5, 144.2, 139.3,138.6 (d), 137.2, 135.7, 134.7 (d), 132.7, 131.9, 131.8, 131.0, 130.7,130.5 (d), 125.5, 124.8, 121.4, 121.3, 118.2 (d), 114.4 (d), 80.8, 21.0,18.2, 17.8

Example 39 Cyclobutanecarboxylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 139)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 301 (920 mg, 2.00mmol) and tetrabutylammonium cyclobutanecarboxylate (1.2 g, 3.5 mmol).The crude product was purified by flash chromatography using diethylether/petroleum ether 1:1 as the eluent to afford the title compound.

¹³C NMR (CDCl₃): δ 196.6, 173.5, 162.1 (d), 152.0, 144.4, 139.2, 138.8,137.2, 135.4, 135.0 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.8, 121.2, 118.0 (d), 114.2 (d), 90.4, 37.7, 25.1, 24.8, 21.0, 19.5,18.4, 17.8

Example 40 3-Methoxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 140)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 301 (920 mg, 2.0 mmol)and tetrabutylammonium 3-methoxy-propionate (1.04 g, 3.0 mmol). Thecrude product was purified by flash chromatography using diethylether/petroleum ether as a gradient from 1:9 to 3:2 as the eluent toafford the title compound.

¹³C NMR (CDCl₃): δ 196.6, 169.7, 162.1 (d), 151.9, 144.3, 139.2, 138.6,137.2, 135.5, 134.9 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 125.5,124.8, 121.3, 118.1 (d), 114.3 (d), 90.5, 67.5, 58.8, 34.8, 21.0, 19.5,17.8

Example 41 2-Acetoxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 141)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 301 (920 mg, 2.0 mmol)and tetrabutylammonium 2-acetoxy-propionate (1.12 g, 3.0 mmol). Thecrude product was purified by flash chromatography using diethylether/petroleum ether as a gradient from 1:9 to 1:1 as the eluent toafford the title compound.

¹³C NMR (CDCl₃): δ 196.5, 170.3, 169.0, 162.2 (d), 151.7, 144.2, 139.3,137.2, 135.6, 134.8, 132.7, 132.3, 131.9, 131.8, 131.0, 130.7, 125.5,124.8, 121.2, 118.1 (d), 114.3 (d), 91.1, 90.8, 68.2, 21.0, 20.6, 19.4,17.8, 16.7, 16.6

Example 42 2,2-Dimethyl-propionic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester (compound 142)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 307 (0.72mL, 1.39 M in THF, 1.00 mmol) and tetrabutylammonium2,2-dimethyl-propionate (516 mg, 1.5 mmol).

¹³C NMR (CDCl₃): δ 196.5, 176.9, 162.2 (d), 152.4, 144.2, 139.3, 138.7(d), 137.2, 135.7, 134.8 (d), 132.7, 131.9, 131.8, 131.0, 130.7, 130.5(d), 125.5, 124.8, 121.2, 118.2 (d), 114.4 (d), 81.2, 38.8, 26.9, 21.0,17.8

Example 43 3-Phenyl-acrylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 143)

The reaction and work up was conducted as described in the preparationof compound 111 except that the reaction was stopped after 4 h. Startingcompounds were compound 301 (920 mg, 2.0 mmol) and tetrabutylammonium3-phenyl-acrylate (1.17 g, 3.0 mmol). The crude product was purified byflash chromatography using diethyl ether/petroleum ether as a gradientfrom 1:9 to 3:2 as the eluent to afford the title compound.

¹³C NMR (CDCl₃): δ 196.6, 164.8, 162.1 (d), 152.0, 146.5, 144.4, 139.2,137.2, 135.5, 135.0 (d), 134.1, 132.7, 131.9, 131.8, 131.0, 130.7,130.6, 129.0, 128.3, 125.5, 124.9, 121.3, 118.1 (d), 116.9, 114.3 (d),90.6, 21.0, 19.7, 17.9

Example 44 Benzoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 144)

The reaction and work up was conducted as described in the preparationof compound 111 except that the reaction was stopped after 1.5 h.Starting compounds were compound 301 (920 mg, 2.0 mmol) andtetrabutylammonium benzoate (1.09 g, 3.0 mmol). The crude product waspurified by flash chromatography using diethyl ether/petroleum ether asa gradient from 1:9 to 2:3 as the eluent to afford the title compound.

¹³C NMR (CDCl₃): δ 196.6, 164.6, 162.1 (d), 152.0, 144.3, 139.2, 138.7,137.2, 135.5, 134.9 (d), 133.6, 132.7, 131.9, 131.8, 131.0, 130.6,129.8, 129.2, 128.5, 125.5, 124.9, 121.3, 118.0 (d), 114.3 (d), 91.0,21.0, 19.7, 17.8

Example 45 Pyridine-2-carboxylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 145)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 301 (920 mg, 2.0 mmol)and tetrabutylammonium pyridine-2-carboxylate (1.09 g, 3.0 mmol). Thecrude product was purified by flash chromatography using diethylether/petroleum ether as a gradient from 1:2 to 1:2 as the eluent toafford the title compound.

¹³C NMR (CDCl₃): δ 196.5, 163.4, 162.1 (d), 152.0, 150.1, 147.2, 144.3,139.2, 138.7, 137.2, 137.1, 135.5, 134.9 (d), 132.7, 131.9, 131.8,131.0, 130.6, 127.3, 125.6, 125.5, 124.9, 121.4, 118.1 (d), 114.3 (d),91.5, 21.0, 19.7, 17.9

Example 46 Isonicotinic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 146)

The reaction and work up was conducted as described in the preparationof compound 111. Starting compounds were compound 301 (920 mg, 2.0 mmol)and tetrabutylammonium isonicotinate (1.09 g, 3.0 mmol). The crudeproduct was purified by flash chromatography using diethylether/petroleum ether as a gradient from 1:2 to 1:2 as the eluent toafford the title compound.

¹³C NMR (CDCl₃): δ 196.5, 163.3, 162.1 (d), 151.8, 150.8, 144.1, 139.3,138.6 (d), 137.1, 136.4, 135.7, 134.8 (d), 132.7, 131.9, 131.8, 131.0,130.7, 130.5 (d), 125.5, 124.9, 122.9, 121.3, 118.1 (d), 114.4 (d),91.4, 21.0, 19.6, 17.9

Example 47 Nicotinic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 147)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (920mg, 2.0 mmol) and tetrabutylammonium nicotinate (1.09 mg, 3.0 mmol).

¹³C NMR (CDCl₃): δ 196.5, 163.4, 162.1 (d), 154.0, 151.0, 144.2, 139.3,138.6, 137.3, 137.1, 135.7, 134.8 (d), 132.7, 131.9, 131.8, 131.0,130.7, 125.5, 125.2, 124.9, 123.4, 121.3, 118.1 (d), 114.4 (d), 91.1,21.0, 19.6, 17.9

Example 48 Nicotinic acid1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 148)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 308 (740mg, 1.5 mmol) and tetrabutylammonium nicotinate (860 mg, 2.4 mmol).

¹³C NMR (CDCl₃): δ 195.4, 163.4, 162.2 (d), 154.0, 151.9, 151.0, 144.4,141.3, 138.6, 138.0, 137.3, 135.6, 135.2, 134.7 (d), 132.7, 132.3,131.8, 130.6, 125.8, 125.2, 124.8, 123.4, 121.3, 118.2 (d), 114.4 (d),91.2, 20.9, 19.6, 17.8

Example 49 2-Hydroxy-benzoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 149)

The reaction and work up was conducted as described in the preparationof compound 111 except that the reaction was stopped after 2 days.Starting compounds were compound 301 (920 mg, 2.0 mmol) andtetrabutylammonium 2-hydroxy-benzoate (1.14 g, 3.0 mmol). The crudeproduct was purified by flash chromatography using diethylether/petroleum ether as a gradient from 5:95 to 1:1 as the eluent toafford the title compound.

¹³C NMR (CDCl₃): δ 196.5, 168.4, 162.2, 162.1 (d), 151.9, 144.1, 139.3,138.7, 137.1, 136.4, 135.7, 134.8 (d), 132.7, 131.9, 131.8, 131.0,130.7, 130.5 (d), 129.9, 125.5, 124.9, 121.3, 119.3, 118.1 (d), 117.8,114.4 (d), 111.5, 90.8, 21.0, 19.6, 17.8

Example 50 Hydroxy-phenyl-acetic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 150)

The reaction and work up was conducted as described in the preparationof compound 111 except that the reaction was stopped after 2 days.Starting compounds were compound 301 (920 mg, 2.0 mmol) andtetrabutylammonium 1-hydroxyl-1-phenyl-acetate (1.12 g, 3.0 mmol). Thecrude product was purified by flash chromatography using diethylether/petroleum ether as a gradient from 1:9 to 1:1 as the eluent toafford the title compound.

¹³C NMR (CDCl₃): δ 196.5, 171.8, 162.2 (d), 151.7, 144.1, 139.3, 138.6,137.6, 137.1, 135.8, 134.7 (d), 132.7, 132.0, 131.8, 131.0, 130.7,130.5, 128.7, 126.6, 125.6, 124.9, 121.3, 118.1 (d), 114.4 (d), 91.5,72.9, 21.0, 19.2, 17.8

Example 51 (S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 151)(diastereomer A)

The reaction, work up and purification was conducted as described in thepreparation of compound 111. Starting compounds were compound 301 (460mg, 1.0 mmol) and tetrabutylammonium(S)-2-tert-butoxycarbonylamino-3-hydroxy-propionate (550 mg, 1.25 mmol).

¹H NMR (CDCl₃): δ 7.55-7.00 (m, 11H), 6.81 (q, 1H), 4.89 (m, 1H), 4.05(m, 1H), 3.58 (m, 2H), 2.44 (s, 3H), 2.14 (bs, 3H), 1.37 (bs, 9H), 1.34(bd, 3H)

Example 52 (S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 152) (diastereomer B)

The title compound was obtained in the above synthesis of compound 151.

¹H NMR (CDCl₃): δ 7.45-7.25 (m, 5H), 7.23-7.08 (m, 3H), 7.07-6.94 (m,2H), 6.91 (q, 1H), 5.40 (bd, 1H), 4.33 (m, 1H), 4.00 (m, 1H), 3.85 (m,1H), 2.53 (s, 3H), 2.32 (bs, 1H), 2.27-2.08 (bs, 3H), 1.50-1.40 (bd,3H), 1.45 (s, 9H)

Example 53 Cream Formulation Containing Compound 112

Butyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (compound 112, 10 g) was dissolved indiethylenglycolmonoethylether (350 g) and distilled water (350 g) wasadded. Methylparaben (1 g) and propylparaben (0.2 g) were dissolved inphenoxyethanol (6 g). This solution was mixed with the former solutionof Compound 101. Paraffin oil (183 g), cetostearylic alcohol (50 g) andARLACEL® (50 g) was melted in a vessel at 70 to 80° C. The mixedsolutions were likewise heated to 60-70° C. and slowly added to themelted oil phase under high speed stirring. The homogenised componentswere cooled to room temperature.

Example 54

EXAMPLE 54 Tablet containing compound 112. Compound 112 (activesubstance)  50 mg Lactose 125 mg Starch  12 mg Methyl cellulose  2 mgSodium carboxymethyl cellulose  10 mg Magnesium stearate  1 mg

The active substance, lactose and starch are mixed to a homogeneousstate in a suitable mixer and moistened with a 5 percent aqueoussolution of methyl cellulose 15 cps. The mixing is continued untilgranules are formed. If necessary, the wet granulation is passed througha suitable screen and dried to a water content of less than 1% in asuitable drier, e.g. fluid bed or drying oven. The dried granules arepassed through a 1 mm screen and mixed to a homogeneous state withsodium carboxymethyl cellulose. Magnesium stearate is added, and themixing is continued for a short period of time. Tablets with a weight of200 mg are produced from the granulation by means of a suitabletabletting machine.

Example 55

EXAMPLE 55 Formulation for injection containing compound 112. Compound112 (active substance) 1% Sodium chloride q.s. Ethanol 10% Water forinjection to make 100%

The active substance is dissolved in ethanol (10%) then water forinjection made isotonic with sodium chloride is added to make 100%. Themixture is filled into ampoules and sterilised.

Example 56 Cream Formulation Containing Compound 112

Compound 112 (10 g) was dissolved in Octyldodecyl myristate (250g) toform Part A. Methylparaben (1 g) and propylparaben (0.2 g) weredissolved in phenoxyethanol (6 g) and mixed with a 0.025 M Phosphatebuffer pH=7.5 (632.8 g) to form Part B. Cetostearyl alcohol (50 g) andARLACEL 165® (50 g) was melted in a vessel at 70° to 80° C. Part A wasadded and heated to 60-70° C. The aqueous phase were likewise heated to60-70° C. and slowly added to the melted oil phase under high speedstirring. The homogenised components were cooled to room temperature.

Example 57 Cream Formulation Containing Compound 112—Pemulen Based

Compound 112 (10 g) was dissolved in Octyldodecyl myristate (250 g) andsorbitan oleate (3 g) was added to form Part A. Pemulen TR-2 (3 g) andCarbopol 980 (3 g) were dispersed in Part A in order to break-up anysoft agglomerates. Methylparaben (1 g) and propylparaben (0.2 g) weredissolved in phenoxyethanol (6 g) and mixed with water (700 g) to formPart B. With moderate agitation Part B was added to Part A and mix 30-40minutes or until a smooth dispersion is apparent. Add as much Sodiumhydroxide in order to obtain a pH of 7.5 and mix vigorously until asmooth product is obtained. Add water to a final volume of 1000 g.

Example 58 Gel Suspension Containing Compound 112

Carbopol 980 (10 g) is dispersed in water (400 g) and neutralised with asodium hydroxide (10%) to pH=7.5 (Part A). In order to prepare Part B,Methylparaben (1 g) and propylparaben (0.2 g) were dissolved inphenoxyethanol (6 g). Methylcellulose (10 g) is dispersed in cold water(100 g) and hot water is added (300 g), which is termed Part C. Part Band Part C is thoroughly mixed and micronized. Compound 101 (10 g) isdispersed in the combined mixture (Part D). Part D is added to theneutralised gel under mild agitation. Water is added to make a finalweight of 1000 gram, the water is thoroughly mixed into the thickenedgel using mild agitation.

Example 59 Gel Formulation Containing Compound 112

Carbopol 980 (10 g) and Aerosil R 972 2% is dispersed in water (600 g)and neutralised with a 10% sodium hydroxide solution to pH=7.5 (Part A).In order to prepare Part B, Methylparaben (1 g) and propylparaben (0.2g) were dissolved in phenoxyethanol (6 g). Compound 112 (10 g) isdissolved in Labrasol (300 g) (Part C). Part B and Part C is combined toform Part D, which is then added to the neutralised gel under mildagitation. Water is added to make a final weight of 1000 g; the water isthoroughly mixed into the thickened gel using mild agitation.

Example 60 Ointment Formulation Containing Compound 112

Compound 112 (5 g) is dissolved in Octyldodecyl myristate (500 g) toform Part A. Aerosil R 972 (70 g) is then dispersed into Part A by lowspeed agitation to form part B. Part B is then combined with Vaseline(380 g).

Example 61 Lotion with Ethanol Containing Compound 112

Compound 112 (5 g) is dissolved in Ethanol (500 g) to form Part A.Polyethylene glycol 300 is then dispersed into Part A by low speedagitation.

Example 62 Lotion with Ethanol Containing Compound 112

Compound 112 (15 g) is dissolved in Ethanol (600 g) and Octyldodecylmyristate (100 g) and Water (300 g) is then added to form Part A.Hydroxypropylmethylcellulose is dispersed into Part A by low speedagitation.

1. A compound of general formula I

wherein R₁ represents a substituent selected from the group consistingof halogen, hydroxy, mercapto, trifluoromethyl, amino, (C₁-C₃)alkyl,(C₂-C₃)olefinic group, (C₁-C₃)alkoxy, (C₁-C₃)alkylthio,(C₁-C₄)alkylamino and cyano; R₂ represents one or more, same ordifferent substituents selected from the group consisting of hydrogen,halogen, hydroxy, mercapto, trifluoromethyl, amino, (C₁-C₃)alkyl,(C₂-C₃)olefinic group, (C₁-C₃)alkoxy, (C₁-C₃)alkylthio,(C₁-C₄)alkylamino, (C₁-C₃)alkoxycarbonyl, cyano, and nitro; R₃represents one or more, same or different substituents selected from thegroup consisting of hydrogen, halogen, hydroxy, mercapto,trifluoromethyl, cyano, carboxy, carbamoyl, (C₁-C₄)alkyl,(C₂-C₄)olefinic group, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, and(C₁-C₄)alkoxycarbonyl; R₄ represents one or more, same or differentsubstituents selected from the group consisting of hydrogen, halogen,hydroxy, mercapto, trifluoromethyl, amino, (C₁-C₃)alkyl, (C₂-C₃)olefinicgroup, (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, (C₁-C₄)alkylamino,(C₁-C₃)alkoxycarbonyl, cyano, and nitro; R₅ represents hydrogen,(C₁-C₆)alkyl and (C₂-C₆)olefinic group; R₆ represents hydrogen,(C₁-C₆)alkyl and (C₂-C₆)olefinic group; R₇ represents (C₁-C₁₈)alkyl,(C₃-C₈)cyclic hydrocarbon group, (C₂-C₁₈)olefinic group, heterocyclyl,(C₂-C₁₈)alkynyl, (C₁-C₁₈)alkyl-heterocyclyl, (C₁-C₁₈)alkyl-(C₃-C₈)cyclichydrocarbon group, (C₂-C₁₈)olefinic group-heterocyclyl, (C₂-C₁₈)olefinicgroup-(C₃-C₈)cyclic hydrocarbon group, (C₂-C₁₈)alkynyl-heterocyclyl,(C₂-C₁₈)alkynyl-(C₃-C₈)cyclic hydrocarbon group; and wherein R₇ mayoptionally be substituted by one or more substituents represented by R₈;R₈ represents halogen, hydroxy, mercapto, trifluoromethyl, amino,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonyl, (C₁-C₉)trialkylammonium in association with apharmaceutically acceptable anion, (C₂-C₁₂)dialkylphosphinoyl,(C₁-C₆)alkyl(hydroxy)phosphinoyl, (C₂-C₁₂)dialkylphosphinoyloxy,(C₁-C₆)alkyl(hydroxy)phosphinoyloxy, dihydroxyphosphinoyl,dihydroxyphosphinoyloxy, cyano, azido, nitro, —CHO, —COOH, —CONH₂,—CONHR′, —CONRR′ wherein R and R′ represent (C₁-C₃)alkyl or Y—R₉; Yrepresents —O—, —S—, —S(O)—, —S(O)₂—, —NR_(a)—, —NR_(a)C(O)NR_(b)—,—NR_(a)C(O)—, —C(O)NR_(a)—, —C(O)—, —C(O)O—, —OC(O)—, —NR_(a)C(O)O—,—OC(O)NR_(a)—, —S(O)₂NR_(a)—, —NR_(a)S(O)₂—, —OC(O)O— or—O(CH₂CH₂O)_(n)— wherein n is an integer between 1 and 6, and R_(a) andR_(b) independently represents hydrogen or (C₁-C₃)alkyl; R₉ represents(C₁-C₆)alkyl, (C₂-C₆)olefinic group, (C₃-C₆)cyclic hydrocarbon group,heterocyclyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-(C₃-C₆)cyclic hydrocarbon or(C₁-C₆)alkyl-heterocyclyl, and wherein R₉ may optionally be substitutedby one or more substituents represented by R₁₀; R₁₀ represents halogen,hydroxy, mercapto, trifluoromethyl, amino, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, (C₁-C₆)alkylamino or (C₁-C₆)alkoxycarbonyl; andpharmaceutically acceptable salts, solvates and hydrates thereof.
 2. Acompound according to claim 1, wherein R₁ represents fluoro, chloro orbromo, methyl or methoxy
 3. A compound according to claim 1 or 2,wherein R₂ represents on or more substituents selected from the listconsisting of hydrogen, fluoro, chloro, methyl or methoxy.
 4. A compoundaccording to claim 1, wherein R₂ represents 2-chloro.
 5. A compoundaccording to 1-4 claim 1, wherein R₃ represents one or more substituentsselected from the list consisting of hydrogen, fluoro, chloro, methyl,ethyl, ethenyl or methoxy.
 6. A compound according to claim 1, whereinR₃ represents 2-methyl and 4-fluoro, or 2-methyl and 4-bromo.
 7. Acompound according to claim 1, wherein R₄ represents one or moresubstituents selected from the list consisting of hydrogen, fluoro,chloro, bromo, methyl and methoxy.
 8. A compound according to claim 1,wherein, R₄ represents 4-chloro.
 9. A compound according to claim 1,wherein R₅ and R₆ each independently represent hydrogen or (C₁-C₆)alkyl.10. A compound according to claim 1, wherein R₅ or R₆ each independentlyrepresents hydrogen, (C₁-C₄)alkyl or methyl.
 11. A compound according toclaim 1, wherein R₇ represents (C₁-C₁₀)alkyl, (C₃-C₆)cyclic hydrocarbongroup, (C₂-C₁₀)olefinic group, heterocyclyl, (C₂-C₁₀)alkynyl,(C₁-C₁₀)alkyl-heterocyclyl, (C₁-C₁₀)alkyl-(C₃-C₆)cyclic hydrocarbongroup, (C₂-C₁₀)olefinic group-heterocyclyl, (C₂-C₁₀), olefinicgroup-(C₃-C₆)cyclic hydrocarbon group, (C₂-C₁₀)alkynyl-heterocyclyl,(C₂-C₁₀)alkynyl-(C₃-C₆)cyclic hydrocarbon group; and wherein R₇ mayoptionally be substituted by one or more substituents represented by R₈.12. A compound according to claim 1, wherein R₇ represents (C₁-C₆)alkyl,(C₃-C₆)cyclic hydrocarbon group, (C₂-C₆)olefinic group, heterocyclyl,(C₂-C₆)alkynyl, (C₁-C₆)alkyl-heterocyclyl, (C₁-C₆)alkyl-(C₃-C₆)cyclichydrocarbon group, (C₂-C₆)olefinic group-heterocyclyl, (C₂-C₆), olefinicgroup-(C₃-C₆)cyclic hydrocarbon group, (C₂-C₆)alkynyl-heterocyclyl,(C₂-C₆)alkynyl-(C₃-C₆)cyclic hydrocarbon group; and wherein R₇ mayoptionally be substituted by one or more substituents represented by R₈.13. A compound according to claim 1, wherein R₇ represents methyl,ethyl, propyl, iso-propyl, butyl, tert-butyl, pentyl, heptyl, nonyl,2-methyl-propyl, 1-methyl-propyl, 2,2-dimethyl-propyl, cyclopropyl,cyclobutyl, phenyl, ethenyl, propenyl, phenylmethyl, phenyl-1-allyl or2-, 3- or 4-pyridyl, all of which may be substituted by R₈.
 14. Acompound according to claim 1, wherein R₈ represents halogen, hydroxy,trifluoromethyl, amino, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonyl, (C₁-C₉)trialkylammonium in association with apharmaceutically acceptable anion, cyano, COOH or Y—R₉.
 15. A compoundaccording to claim 1, wherein R₈ represents hydroxyl or carboxy.
 16. Acompound according to claim 1, wherein Y represents —O—, —NR_(a)—,—NR_(a)C(O)—, —C(O)NR_(a)—, —C(O)—, —C(O)O—, —OC(O)—, —NR_(a)C(O)O— or—O(CH₂CH₂O)_(n)— wherein n is 1, 2, 3 or 4, and R_(a) and R_(b) bothrepresents hydrogen.
 17. A compound according to claim 1, wherein Yrepresents —C(O)—O—, NH—C(O)—O—, —O—, —O—C(O)— or —O(CH₂CH₂O)_(n)—wherein n is
 3. 18. A compound according to claim 1, wherein R₉represents (C₁-C₄)alkyl, (C₂-C₃)olefinic group, (C₃-C₆)cyclichydrocarbon group, heterocyclyl, (C₂-C₃)alkynyl,(C₁-C₃)alkyl-(C₃-C₆)cyclic hydrocarbon or (C₁-C₃)alkyl-heterocyclyl,wherein R₉ may optionally be substituted by one or more substituentsrepresented by R₁₀.
 19. A compound according to claim 1, wherein R₉represents (C₁-C₄)alkyl or (C₁-C₃)alkyl-(C₃-C₆)cyclic hydrocarbon.
 20. Acompound according to claim 1, wherein R₉ represents methyl, ethyl,tert-butyl or phenylmethyl.
 21. A compound according to claim 1, whereinR₁₀ represents fluoro, chloro, hydroxy, trifluoromethyl, amino,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylamino or (C₁-C₃)alkoxycarbonyl.22. A compound according to claim 1, wherein R₁ is methyl; R₂ is2-chloro; R₃ is 2-methyl and 4-fluoro, or 2-methyl and 4-bromo; R₄ ishydrogen or 4-chloro; R₅ and R₆ independently represent hydrogen or(C₁-C₄)alkyl; R₇represents (C₁-C₁₀)alkyl, (C₃-C₆)cyclic hydrocarbongroup, (C₂-C₁₀)olefinic group, heterocyclyl, (C₂-C₁₀)alkynyl,(C₁-C₁₀)alkyl-heterocyclyl, (C₁-C₁₀)alkyl-(C₃-C₆)cyclic hydrocarbongroup, (C₂-C₁₀)olefinic group-heterocyclyl, (C₂-C₁₀), olefinicgroup-(C₃-C₆)cyclic hydrocarbon group, (C₂-C₁₀)alkynyl-heterocyclyl,(C₂-C₁₀)alkynyl-(C₃-C₆)cyclic hydrocarbon group; and wherein R₇ mayoptionally be substituted by one or more substituents represented by R₈;R₈ represents halogen, hydroxy, trifluoromethyl, amino, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino, (C₁-C₆)alkoxycarbonyl,(C₁-C₉)trialkylammonium in association with a pharmaceuticallyacceptable anion, cyano, —COOH or Y—R₉; Y represents —O—, —NR_(a)—,—NR_(a)C(O)—, —C(O)NR_(a)—, —C(O)—, —C(O)O—, —OC(O)—, —NR_(a)C(O)O— or—O(CH₂CH₂O)_(n)— wherein n is 1, 2, 3 or 4, and R_(a) and R_(b) bothrepresents hydrogen; R₉ represents (C₁-C₃)alkyl, (C₂-C₃)olefinic group,(C₃-C₆)cyclic hydrocarbon group, heterocyclyl, (C₂-C₃)alkynyl,(C₁-C₃)alkyl-(C₃-C₆)cyclic hydrocarbon or (C₁-C₃)alkyl-heterocyclyl,wherein R₉ may optionally be substituted by one or more substituentsrepresented by R₁₀; R₁₀represents fluoro, chloro, hydroxy,trifluoromethyl, amino, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylaminoor (C₁-C₃)alkoxycarbonyl; and pharmaceutically acceptable salts solvatesor hydrates thereof.
 23. A compound according to claim 1, wherein R₁ ismethyl; R₂ is 2-chloro; R₃ is 2-methyl and 4-fluoro, or 2-methyl and4-bromo; R₄ is hydrogen or 4-chloro; R₅ and R₆ independently representhydrogen or (C₁-C₄)alkyl; R₇ represents (C₁-C₆)alkyl, (C₃-C₆)cyclichydrocarbon group, (C₂-C₆)olefinic group, heterocyclyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-heterocyclyl, (C₁-C₆)alkyl-(C₃-C₆)cyclic hydrocarbon group,(C₂-C₆)olefinic group-heterocyclyl, (C₂-C₆), olefinicgroup-(C₃-C₆)cyclic hydrocarbon group, (C₂-C₆)alkynyl-heterocyclyl,(C₂-C₆)alkynyl-(C₃-C₆)cyclic hydrocarbon group; and wherein R₇ mayoptionally be substituted by one or more substituents represented by R₈;R₈represents halogen, hydroxy, trifluoromethyl, amino, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino, (C₁-C₆)alkoxycarbonyl,(C₁-C₉)trialkylammonium in association with a pharmaceuticallyacceptable anion, cyano, —COOH or Y—R₉; Y represents —O—, —NR_(a)—,—NR_(a)C(O)—, —C(O)NR_(a)—, —C(O)—, —C(O)O—, —OC(O)—, —NR_(a)C(O)O— or—O(CH₂CH₂O)_(n)— wherein n is 1, 2, 3 or 4, and R_(a) and R_(b) bothrepresents hydrogen; R₉ represents (C₁-C₃)alkyl, (C₂-C₃)olefinic group,(C₃-C₆)cyclic hydrocarbon group, heterocyclyl, (C₂-C₃)alkynyl,(C₁-C₃)alkyl-(C₃-C₆)cyclic hydrocarbon or (C₁-C₃)alkyl-heterocyclyl,wherein R₉ may optionally be substituted by one or more substituentsrepresented by R₁₀; R₁₀represents fluoro, chloro, hydroxy,trifluoromethyl, amino, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylaminoor (C₁-C₃)alkoxycarbonyl; and pharmaceutically acceptable salts solvatesor hydrates thereof.
 24. A compound according to claim 1, wherein R₁ ismethyl; R₂ is 2-chloro; R₃ is 2-methyl and 4-fluoro, or 2-methyl and4-bromo; R₄ is hydrogen or 4-chloro; R₅ and R₆ independently representhydrogen or methyl; R₇ represents methyl, ethyl, propyl, iso-propyl,butyl, tert-butyl, pentyl, heptyl, nonyl, 2-methyl-propyl,1-methyl-propyl, 2,2-dimethyl-propyl, cyclopropyl, cyclobutyl, phenyl,ethenyl, propenyl, phenylmethyl, phenyl-1-allyl or 2-, 3- or 4-pyridyl,all of which may be substituted by R₈; R₈ represents hydroxyl, carboxy;Y represents —C(O)—O—, NH—C(O)—O, —O—, —O—C(O)— or —O(CH₂—CH₂—O)_(n)—, nbeing 3; R₉ represents methyl, ethyl, tert-butyl or phenylmethyl; R₁₀represents fluoro, chloro, hydroxy, trifluoromethyl, amino,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylamino or (C₁-C₃)alkoxycarbonyl;and pharmaceutically acceptable salts, solvates and hydrates thereof.25. A compound according to claim 1 selected from the group consistingof Succinic acid benzyl ester1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Succinic acidmono-{1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethyl}ester;Sodium3-{1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethoxycarbonyl}-propionate;{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; {2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethylester; Succinic acid benzyl ester1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethylester; Succinic acidmono-(1-{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-ethyl)ester; Succinic acid{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-methylester methyl ester; Succinic acid benzyl ester{(4-bromo-2-methyl-phenyl)-[3-chloro-4-(2-methyl-benzoyl)-phenyl]-carbamoyloxy}-methylester; Acetic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Butyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Butyric acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester; Pentanoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Hexanoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Octanoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Decanoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Succinic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester ethyl ester; Methoxy-acetic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Methoxy-acetic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester; Butyric acid1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 3-Methoxy-propionic acid1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 3,3-Dimethyl-butyric acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester; Cyclopropanecarboxylic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester; Cyclobutanecarboxylic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester; 2-Hydroxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 2-Methyl-but-2-enoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 2-Hydroxy-2-methyl-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 2-Hydroxy-2-methyl-propionic acid1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Isobutyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Isobutyric acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester; 2,2-Dimethyl-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 3-Methyl-butyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 2-Methyl-butyric acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Cyclopropanecarboxylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Acrylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; But-2-enoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; But-2-enoic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester; Cyclobutanecarboxylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 3-Methoxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 2-Acetoxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 2,2-Dimethyl-propionic acid[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-methylester; 3-Phenyl-acrylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Benzoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Pyridine-2-carboxylic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Isonicotinic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Nicotinic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Nicotinic acid1-[[3-chloro-4-(4-chloro-2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; 2-Hydroxy-benzoic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; Hydroxy-phenyl-acetic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester; (S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (diastereomer A); and(S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid1-[[3-chloro-4-(2-methyl-benzoyl)-phenyl]-(4-fluoro-2-methyl-phenyl)-carbamoyloxy]-ethylester (diastereomer B).
 26. A compound according to claim 1 for use intherapy.
 27. A pharmaceutical composition comprising a compoundaccording to claim 1, optionally together with another therapeuticallyactive compound, and one or more pharmaceutically acceptable carriers orexcipients.
 28. A formulation according to claim 27, wherein said othertherapeutically active compound is selected from the list consisting ofglucocorticoids, vitamin D analogues, anti-histamines, plateletactivating factor (PAF) antagonists, anticolinergic agents, methylxanthines, β-adrenergic agents, COX-2 inhibitors, salicylates,indomethacin, flufenamate, naproxen, timegadine, gold salts,penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts,and salicylazosulfapyridin (Salazopyrin).
 29. A method for the treatmentof acne, atopic dermatitis, contact dermatitis, psoriasis, asthma,allergy, arthritis, rheumatoid arthritis, spondyloarthritis, gout,atherosclerosis, chronic inflammatory bowel disease, uveitis and septicshock, the method comprising administering to a patient in need thereofan effective amount of a compound according to claim 1, optionally incombination with another therapeutically active compound.
 30. A methodaccording to claim 29, wherein said other therapeutically activecompound is selected from the list consisting of glucocorticoids,vitamin D analogues, anti-histamines, platelet activating factor (PAF)antagonists, anticolinergic agents, methyl xanthines, β-adrenergicagents, COX-2 inhibitors, salicylates, indomethacin, flufenamate,naproxen, timegadine, gold salts, penicillamine, serumcholesterol-reducing agents, retinoids, zinc salts, andsalicylazosulfapyridin (Salazopyrin).
 31. The use of a compoundaccording to claim 1 in the manufacture of a medicament for thetreatment of acne, atopic dermatitis, contact dermatitis, psoriasis,asthma, allergy, arthritis, rheumatoid arthritis, spondyloarthritis,gout, atherosclerosis, chronic inflammatory bowel disease, uveitis orseptic shock.